Implantable cranial medical device

ABSTRACT

An implantable cranial medical device includes a first fluid flow path, a second fluid flow path, and upper flange portion, and a lower portion. The upper flange portion is configured to rest on a skull of a subject about a burr hole. The lower portion is configured to be placed within the burr hole. The first fluid flow path may extend from a first opening in the upper flange portion to a first opening in the lower portion. The second fluid flow path may extend from a second opening in the upper flange portion to a second opening in the lower portion.

RELATED APPLICATIONS

This application is a continuation of U.S. Application No. 17/376,530,filed Jul. 15, 2021, which claims the benefit of U.S. Provisional Pat.Application No. 63/052,284, filed on Jul. 15, 2020, and U.S. ProvisionalPat. Application No. 63/209,835, filed on Jun. 11, 2021, whichprovisional patent applications are hereby incorporated herein byreference in their respective entireties to the extent that they do notconflict with the disclosure presented herein.

FIELD

The present disclosure relates to, among other things, implantablecranial medical devices, such as devices for delivering fluid tocerebrospinal fluid (CSF), such as cerebral ventricles, withdrawing ordraining fluid from CSF, such as cerebral ventricles, or deliveringfluid to CSF and withdrawing or draining fluid from CSF.

INTRODUCTION

Delivery of therapeutic agents to the central nervous system (CNS) andtreatment of diseases of the CNS present challenges. For example, manytherapeutic agents are not able to reach the brain at therapeuticconcentrations when administered through traditional routes due to theblood-brain-barrier (BBB). In addition, systemic concentrations oftherapeutic agents, or metabolites or degradation products thereof, maybe undesirably high to achieve therapeutic levels in the brain whentherapeutic agents that do cross the BBB are systemically administered.

Some devices and therapies have been developed to administer therapeuticagents to CSF to address some of these challenges. Such devices andtherapies have typically been configured to deliver a bolus oftherapeutic agent to a cerebral ventricle or to chronically administerthe therapeutic agent to intrathecal space of the spinal canal. Suchapproaches have shortcomings for treatment of diseases of the brain. Forexample, such approaches lack the ability to achieve adequate spatiallyand temporally exposure of a therapeutic agent. Bolus administration ofa therapeutic agent may not provide consistent therapeutically effectiveconcentrations of the therapeutic agent, and intrathecal administrationmay not provide for sufficiently high concentrations of therapeuticagent in the brain due to, for example, gravitational forces andrelatively limited CSF circulation.

Monitoring of a state a disease, subject or therapy, such asconcentrations of therapeutic agents in the brain, may also presentchallenges. For example, accurate estimates of concentrations oftherapeutic agents in the brain may not always be readily achievedthrough routine blood or urine analysis. In addition, withdrawing CSF toobtain more accurate estimates of central therapeutic agentconcentrations is invasive and may present risks.

For those therapies that include direct intracerebral ventriculardelivery of therapeutic agents through, for example, an implantableinfusion pump or port, CSF may be withdrawn through a catheterconfigured to deliver the therapeutic agent to the CSF from the pump orport. However, withdrawing CSF through the same lumen of a catheter thathas been used to deliver therapeutic agent may not provide a cleansample of CSF. That is, the CSF may include therapeutic agent that waspresent in the lumen of the catheter and thus may not provide foraccurate estimates of concentration of the therapeutic agent in the CSF.In addition, the CSF or the components of the CSF that maybe measuredmay interact with the material defining the lumen of the catheter, whichmay adversely affect subsequent delivery of the therapeutic agent.Furthermore, withdrawing CSF through the same lumen of the catheter thathas been used to delivery therapeutic agent requires an interruption inthe delivery of the therapeutic agent. The interruption of delivery canlead to cessation of therapy and other substantial consequences.

The use of separate catheters or separate lumens of a catheter fordelivering therapeutic agents to the cerebral ventricles and forwithdrawing CSF from the cerebral ventricles has been proposed. However,designing and manufacturing devices, such as access ports, that maycouple to two or more catheters or a catheter having more than one lumenfor delivering fluid to or from cerebral ventricles presents challenges,particularly if the devices are configured to be implanted under thescalp or skin of a subject. For example, a subject, such as a humanpatient, may tolerate a limited height of a device, such as a port thatis coupled to the catheter or catheters, above the skull when the deviceis implanted under the scalp. In addition, devices implanted under thescalp or skin should have an external shape and profile configured tominimize erosion of the skin and patient discomfort and facilitate safeand efficient surgical implantation. An additional challenge relates toensuring a secure connection between catheters and the devices to whichthey are connected. For example, it may be difficult to couple acatheter to an access port after the port is positioned in a subject.Further challenges relate to reproducible access to the implanted port.For example, proper positioning of the port should be maintained toensure repeated access through the skin of a subject over extendedperiods of time. Such challenges result from the limited space availablefor such devices to be implanted, multifunctionality of the devices, andthe need for secure connection between a catheter and the access port.

At least in part because of these challenges, a device of suitable size,shape, and functionality for connecting to more than one catheter or acatheter with more than one lumen for delivering fluid to or from a CSFspace, such as a cerebral ventricle, of a subject has not previouslybeen developed.

SUMMARY

The present application relates to, among other things, an implantablecranial device that comprises two or more separate fluid flow paths. Theimplantable cranial device may be coupled to multiple single lumencatheters, to one or more multi-lumen catheters, or to one or moresingle lumen catheters and to one or more multi-lumen catheters, witheach lumen being independently in fluid communication with one of theseparate fluid flow paths. One or more of the separate fluid flow pathsmay be used, for example, to deliver therapeutic agents to a cerebralventricle through one or more lumens of one or more catheters. One ormore of the separate fluid flow paths may be used, for example, towithdraw CSF from a cerebral ventricle through one or more lumens of theone or more catheters.

The implantable cranial device is able to accommodate multiple separatefluid flow paths, in part, because a portion of the device is configuredto be implanted within a burr hole in a skull and a portion isconfigured to be implanted between the skull and the scalp. The addedspace afforded by the portion implanted within the burr hole permits theimplantable cranial device to include multiple separate fluid flowpaths, while meeting design considerations to allow for safe andefficient implantation under the scalp.

According to an aspect of the present disclosure, an implantable cranialmedical device comprises a first fluid flow path, a second fluid flowpath, an upper flange portion, and a lower portion. The upper flangeportion is configured to rest on a skull of a subject about a burr hole.The lower portion is configured to be placed within the burr hole. Thefirst fluid flow path extends from a first opening in the upper flangeportion to a first opening in the lower portion. The second fluid flowpath extends from a second opening in the upper flange portion to asecond opening in the lower portion.

According to another aspect of the present disclosure, an implantablecranial medical device comprises a first fluid flow path, a second fluidflow path, an upper flange portion, and a lower flange portion. Theupper flange portion has a width in a range from 15 millimeters to 30millimeters. The lower portion has a width in a range from 10millimeters to 20 millimeters. The upper flange portion has a greaterwidth than the lower portion. The first fluid flow path extends from afirst opening in the upper flange portion to a first opening in thelower portion. The second fluid flow path extends from a second openingin the upper flange portion to a second opening in the lower portion.

The implantable cranial devices may include, or may be configured to becoupled to, for example, multiple single lumen catheters or to amulti-lumen catheter at, for example, the bottom of the lower portionsuch that one catheter lumen is in communication with the first fluidflow path and another catheter lumen is in communication with the secondfluid flow path. Preferably, the catheter or catheters are coupled tothe implantable cranial medical device prior to implanting in a subjectto avoid problems with securely connecting the catheter or catheters tothe implantable cranial medical device after the distal ends of thecatheters have been positioned in the subject. More preferably, theimplantable cranial medical device includes the catheter or catheters,or the catheter or catheters are coupled to the implantable cranialmedical device by a manufacturer, to ensure secure connection of thecatheter or catheters. Preferably, the catheter is a multi-lumencatheter because placement and implantation of multiple catheters mayadd surgical complexity.

At least one lumen of at least one catheter may be placed in fluidcommunication with a subject’s CSF such that fluid may be delivered toor withdrawn from the subject’s CSF through the first or second flowpath of the implantable cranial medical device. In some embodiments,first and second lumens of one or more catheters are placed in fluidcommunication with a cerebral ventricle of a subject such that fluid maybe delivered to or withdrawn from the cerebral ventricle through thefirst and second flow paths of the implantable cranial medical device.The catheter or catheters are preferably configured such that fluid maybe delivered to or withdrawn from the cerebral ventricle through one ofthe first and second flow paths of the implantable cranial medicaldevice without interference or mixing of the fluids that are beingdelivered to, or withdrawn from, the cerebral ventricle through theother of the first and second flow paths. In some embodiments, thecatheters or catheters are configured such that one lumen may deliverfluid to brain tissue other than a cerebral ventricle and another lumenmay deliver fluid to or withdraw fluid from a cerebral ventricle.

Also provided herein are methods of implanting the implantable cranialmedical devices and associated catheter or catheters, as well as methodsof treating, monitoring, or treating and monitoring a disease of stateof a subject using the implantable cranial medical devices.

The details of one or more aspects of the disclosure are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the techniques described in this disclosurewill be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic side view of an embodiment of an implantablecranial medical device.

FIG. 2 is a schematic bottom view of an embodiment of the implantablecranial medical device depicted in FIG. 1 .

FIG. 3 is a schematic top view of an embodiment of the implantablecranial medical device depicted in FIGS. 1 and 2 .

FIG. 4 is a schematic side view of an embodiment of an implantablecranial medical device.

FIG. 5 is a schematic top view of an embodiment of the implantablecranial medical device depicted in FIG. 4 .

FIG. 6 is a schematic side view of the implantable cranial medicaldevice depicted in FIG. 4 in which the housing is sectioned.

FIG. 7 is a schematic perspective view showing a bottom of an embodimentof the implantable cranial medical device depicted in FIGS. 4-6 .

FIG. 8 is a schematic cross-sectional view of an embodiment of a duallumen brain catheter.

FIG. 9 is a schematic longitudinal sectional view of a distal portion ofa brain catheter.

FIG. 10 is a schematic longitudinal sectional view of a distal portionof a brain catheter.

FIG. 11 is an exploded perspective view of an embodiment of animplantable cranial medical device showing components of a port and anexternal catheter connector.

FIG. 12 is a photograph of a cut away of a housing of an embodiment ofan implantable cranial medical device.

FIG. 13 is a perspective view of an embodiment of an implantable cranialmedical device coupled to a brain catheter and a stylet employed forimplanting the brain catheter while the brain catheter is coupled to theimplantable cranial medical device.

FIG. 14 is a schematic sectional view illustrating an embodiment of animplantable cranial medical device, brain catheter, and externalcatheter implanted in a patient.

FIG. 15 is a schematic sectional view illustrating some components of anembodiment of implantable cranial device with fluid flow pathways shownin dashed lines.

FIG. 16 is a schematic drawing of a system including an implantablecranial medical device and an external device.

FIG. 17 is a schematic drawing of a system including an implantablecranial medical device and two external devices.

FIGS. 18-21 are schematic illustrations of some components ofembodiments of systems described herein.

FIG. 22 is a schematic sectional view of embodiments of a port that maybe connected to an implantable cranial medical device.

FIG. 23 is a schematic drawing showing infusion of agents into acerebral ventricle and aspiration of cerebral spinal fluid from theventricle using a catheter according to an embodiment of the invention.

FIG. 24 is an image of an embodiment of an implantable cranial deviceimplanted in a skull of a patient.

While the invention is susceptible to various modifications andalternative forms, specific embodiments thereof are shown by way ofexample in the drawings and may herein be described in detail. Thedrawings may not be to scale. It should be understood, however, that thedrawings and detailed description thereto are not intended to limit theinvention to the particular form disclosed, but on the contrary, theintention is to cover all modifications, equivalents and alternativesfalling within the spirit and scope of the present invention as definedby the appended claims.

Like numbers used in the figures refer to like components and steps.However, it will be understood that the use of a number to refer to acomponent in a given figure is not intended to limit the component inanother figure labeled with the same number. In addition, the use ofdifferent numbers to refer to components in different figures is notintended to indicate that the different numbered components cannot bethe same or similar to other numbered components

DETAILED DESCRIPTION

The present disclosure relates to, among other things, an implantablecranial medical device. The implantable cranial medical device comprisesfirst and second fluid flow paths. The fluid flow paths are separate andisolated. The implantable cranial medical device may comprise one ormore catheters, or may be configured to operably couple to one or morecatheters, for delivering fluid to, or withdrawing fluid from, a tissueor fluid of a central nervous system of a subject. Preferably, theimplantable cranial medical device includes a multi-lumen catheter or isconfigured to operably couple to a multi-lumen catheter, where a firstlumen of the multi-lumen catheter is in fluid communication with thefirst fluid flow path and a second lumen of the multi-lumen catheter isin fluid communication with the second fluid flow path. The first fluidflow path and the first lumen may be configured to deliver fluid to, orwithdraw fluid from, a first target brain location. The second fluidflow path and the second lumen may be configured to deliver fluid to, orwithdraw fluid from, a second target brain location. The first andsecond target brain locations may be the same or different.

Preferably, at least one of: (i) the first fluid flow path and firstlumen; and (ii) the second fluid flow path and second lumen, isconfigured to withdraw CSF from a subject, for example, from a cerebralventricle. For purposes of the present disclosure, withdrawing CSF froma CSF-containing space, such as a cerebral ventricle, includesaspirating or draining CSF from the CSF-containing space. In someembodiments, both (i) the first fluid flow path and first lumen and (ii)the second fluid flow path and second lumen, are configured to deliverfluid to, or withdraw fluid from, a CSF-containing space of a subject.Preferably, one fluid flow path and lumen are used to deliver fluid to aCSF-containing space, such as a cerebral ventricle, and the other fluidflow path and lumen are used to withdraw fluid from a CSF-containingspace, such as a cerebral ventricle.

The implantable cranial device is able to accommodate multiple separatefluid flow paths, in part, because a portion of the device is configuredto be implanted within a burr hole in a skull and a portion isconfigured to be implanted between the skull and the scalp. The addedspace afforded by the portion implanted within the burr hole permits theimplantable cranial device to include multiple separate fluid flowpaths, while meeting design considerations to allow for safe andefficient implantation under the scalp.

The implantable cranial medical device comprises an upper flange portionand a lower portion. The lower portion may be sized and shaped to bedisposed within a burr hole in a skull of a subject. Accordingly, thesize and shape of the lower portion may vary depending on the size andshape of the burr hole, or the size of the burr hole may be determinedby the size and shape of the lower portion. Preferably, the clearancebetween an exterior side surface of the lower portion and the skull issmall when the lower portion is positioned in the burr hole. The smallerthe clearance between the skull and the exterior side surface of thelower portion, the larger the volume of the lower portion. Largervolumes of the lower portion may facilitate incorporation of both thefirst and second flow paths within the device. Smaller clearancesbetween the exterior side surface of the lower portion and the burr holealso improve stability of the implantable cranial device relative to theskull. Improved stability may be manifest in less movement of theimplantable cranial device relative to the skull.

In some embodiments, the clearance between the exterior side surface ofthe lower portion and the skull, when the lower portion is disposed inthe burr hole, is between 0 mm and 5 mm. For example, the clearancebetween the exterior side surface of the lower portion and the skull,when the lower portion is disposed in the burr hole, may be between 0.1mm and 3 mm, such as between 0.2 mm and 2 mm.

In some embodiments, the lower portion has a width in a range from about10 millimeters to about 20 millimeters. For example, the lower portionof the housing may have a width in a range from about 10 millimeters toabout 14 millimeters, such as from about 11 millimeters to about 13millimeters. A burr hole typically is cylindrical. In some embodiments,the burr hole may have a diameter of about 14 millimeters. The lowerportion of the device may have a generally circular cross-section, andthe width of the lower portion may be a diameter.

When the implantable cranial medical device is implanted, a bottom majorsurface of the lower portion preferably does not extend substantiallybeyond the bottom of the burr hole. Accordingly, the height of the lowerportion of the housing of the implantable cranial medical device mayvary depending on the thickness of the skull of the subject into whichthe device is implanted. As an example, a thickness of a human adultskull may typically be in a range from about 6.5 millimeters to about 7millimeters.

In some embodiments, the height of the lower portion of the implantablecranial medical device is in a range from about 3 millimeters to about 7millimeters. For example, the height of the lower portion may be in arange from about 4 millimeters to about 6 millimeters or from about 4.5millimeters to about 5.5 millimeters.

The upper flange portion is preferably configured to rest on a skull ofa subject above the burr hole. For purposes of this disclosure, theupper flange portion will be considered to rest on the skull if one ormore intervening structures are placed between the bottom of the upperflange portion and the skull. The upper flange portion preferably has awidth greater than the burr hole so that the upper flange portion mayrest on the skull above the burr hole when the lower portion ispositioned in the burr hole. Accordingly, the upper flange portionpreferably has a width greater than the lower portion.

The upper flange portion may have a top surface and a bottom surface.The bottom surface of the upper flange portion may laterally extendrelative to the lower portion. The bottom surface of the upper flangeportion may be annular. The bottom surface of the upper flange portionmay be generally flat. For purposes of the present disclosure,“generally flat,” in the context of the bottom surface of the upperflange portion includes slightly curved to approximate curvature of askull. The bottom surface may be generally flat and annular.

The upper flange portion may have any suitable width. In someembodiments, the width is defined by the bottom surface of the upperflange portion. In some embodiments, the upper flange portion has awidth in a range from about 15 millimeters to about 30 millimeters. Forexample, the upper flange portion may have a width in a range from about18 millimeters to about 28 millimeters, or from about 22 millimeters toabout 26 millimeters. The upper flange portion may have an outer surfacethat has a generally circular cross section. Accordingly, the width ofthe upper flange portion may be a diameter.

The upper flange portion may have any suitable height. Preferably, theheight of the upper flange portion is sufficiently small to be welltolerated by a subject when the implantable cranial medical device isimplanted under a scalp of the subject. The height of the upper flangeportion may define the distance that the implantable cranial medicaldevice extends above the skull when implanted in the subject.

In some embodiments, the height of the upper flange portion of theimplantable cranial medical device is in a range from about 3millimeters to about 8 millimeters. For example, the height of the upperflange portion may be in a range from about 4 millimeters to about 6.5millimeters or from about 5 millimeters to about 6.5 millimeters.

The implantable cranial medical device may have any suitable overallheight. In some embodiments, the height of the device from the bottom ofthe lower portion to the top of the upper flange portion of the housingis in a range from about 6 millimeters to about 15 millimeters, such asfrom about 8 millimeters to about 12 millimeters.

The top surface of the upper flange portion may have any suitable shape.Preferably, the top surface or the transition from a side surface to thetop surface has no sharp edges. In some embodiments, the top surface ofthe housing has a generally convex shape.

In some embodiments, the bottom surface of the upper flange portion ofthe housing is generally flat and annular and the top surface isgenerally convex.

In some embodiments, the thickness or height of the upper flange portionincreases moving from an outer edge of the upper flange portion towardsthe center the upper flange portion.

The implantable cranial medical device may comprise a housing. Thehousing may define an exterior surface of the device. The housing maydefine an external surface of the upper flange portion and an externalsurface of the lower flange portion.

The housing may be formed from one or more parts. In some embodiments,the housing comprises a single part that defines the exterior surfacethe upper flange portion and the lower portion of the housing. Thehousing may be formed from more than one part, the parts may beconnected in any suitable manner. As an example, different parts of thehousing may be secured relative to one another by threaded engagement,snap fit engagement, interference fit engagement, may be welded,adhered, or otherwise bonded to one another, or the like, orcombinations thereof. Preferably, different parts of the housing areconnected to one another in a fluid tight manner. Preferably, differentparts of the housing are welded together.

The housing of the implantable cranial medical device may comprise anysuitable material. For example, the housing of the implantable cranialmedical device may be formed from one or more of a metallic material, aplastic material, a ceramic material, and a glass material. For example,the housing may comprise one or more of a high performance thermoplasticor relatively rigid plastic material, such as polyurethane,polycarbonate, polysulfone, polyether ether ketone (PEEK), nylon, andUltra High Molecular Weight Polyethylene (UHMWPE); and a biocompatiblemetal, such as a stainless steel alloy, titanium, and nitinol.Preferably, the material is compatible with magnetic resonance imaging(MRI). Preferably, the housing comprises a biocompatible material orcomprises an exterior biocompatible coating.

In some embodiments, implantable cranial medical device comprises asleeve configured to cover one or more portions of the housing. Thesleeve may be formed from one or more materials that are softer, morecompliant, or softer and more compliant than the housing. The sleeve maybe formed from any suitable material or materials. For example, thesleeve may comprise one or more of silicone and a thermoplasticelastomer. The sleeve is preferably biocompatible. The sleeve may becoated with or comprise a lubricious material, such as a hydrogel. Thesleeve may serve to absorb impact that may occur to the patient’s skinover the implantable cranial medical device, which may reduce potentialdamage to the device or the patient. The sleeve may serve to reducetissue erosion over time, particularly if the sleeve is formed fromlubricious material or a material that is softer or more compliant thanthe housing. The sleeve may comprise one or more antimicrobial agent,such as antimicrobial silver and antibiotics. For example, the sleevemay be impregnated with one or antibiotics, such as minocycline andrifampin.

The first and second fluid flow paths of the implantable cranial medicaldevice may be configured in any suitable manner. Preferably, the firstand second fluid flow paths each extend within an interior of thehousing, from the upper flange portion of the device to the lowerportion of the device. For example, the first fluid flow path may extendfrom a first opening in the upper flange portion to a first opening inthe lower portion, and the second fluid flow path may extend through thehousing from a second opening in the upper flange portion to a secondopening in the lower portion.

The fluid flow paths may be formed in any suitable manner and form anysuitable material or materials. The fluid flow paths, or portionsthereof, may comprise passageways formed from one or more parts. In someexamples, the passageway is formed from a lumen within tubing. In someexamples, the passageway is formed from a channel in a solid part thatis coupled to a second part to enclose the passageway. In someembodiments, the fluid flow paths are formed by the housing. Forexample, the fluid flow paths may be formed in a mold of the housing,micromachined in a component of the housing, may be formed by voidspaced generated by assembling components of the housing, or the like.Preferably, the material lining the passageway is compatible with fluidthat flows through the passageway, such as a fluid containing atherapeutic agent or CSF. Preferably, the therapeutic agent orexcipients or CSF do not sorb to or react with the material defining thepassageway. For purposes of the present disclosure, “sorb” refers to oneor both of adsorb and absorb.

The structural material forming the passageway may be compatible withthe fluid or the structural material may be coated with a compatiblematerial.

Any suitable material or material may define the fluid flow paths of theimplantable cranial medical device. In some embodiments, the materialdefining the fluid flow paths comprises one or more of metallicmaterial, polymeric material, ceramic material, or glass material. Forexample, the material defining the fluid flow paths may comprise one ormore of a high performance thermoplastic or relatively rigid plasticmaterial, such as polyurethane, polycarbonate, polysulfone, polyetherether ketone (PEEK), nylon, and Ultra High Molecular Weight Polyethylene(UHMWPE); and a biocompatible metal, such as a stainless steel alloy,titanium, and nitinol.

The implantable cranial medical device may comprise one or more filterpositioned and arranged to filter fluid flowing through the first fluidflow path, the second fluid flow path, or the first and second fluidflow paths. Preferably the filter has a pore size of 0.45 microns orless, such as 0.22 microns or less, or 0.2 microns or less. Filtershaving pore sizes of 0.45 microns or less may effectively filtermicrobes, such as bacteria. Filters having pore sizes of 0.22 microns orless mat effectively filter viruses.

Preferably, a fluid flow path that is configured for withdrawing(aspirating) CSF does not comprise a microbial filter. The ability towithdraw CSF through a microbial filter over time may diminish if amicrobial filter is present in a passageway through which the CSF iswithdrawn. The ability to withdraw CSF through a microbial filter overtime may be due to accumulation of cells and CSF proteins on the filterover time, which may clog the filter. Diminished ability to withdraw CSFthrough the first fluid pathway of the device may reduce usability ofthe device (e.g., only a fluid delivery pathway may remain useable). Inaddition, if a microbial infection is present in the CSF, the microberesponsible for the infection may be removed from the CSF if it werepassed through a microbial filter. Thus, the presence of a microbialfilter in a fluid flow path configured to withdraw CSF may prevent theability to detect an infection in withdrawn CSF. For at least thesereasons, a fluid flow path configured to withdraw CSF preferably doesnot include a microbial filter.

In some embodiments, the second fluid flow path comprises a microbialfilter and the first fluid flow path does not include a microbialfilter. The first fluid flow path may be configured for withdrawal ofCSF. The second fluid flow path may be configured for introduction oftherapeutic fluid.

The implantable cranial medical device may comprise any suitableconnector or port to permit fluid to flow to or from a flow path of thedevice through a separate device, such as a catheter, needle, or thelike. The connector or port may be formed, at least in part, the upperflange portion or the lower portion of the device. For example, thefirst or second openings of the upper flange portion or the lowerportion may define the connector or port, or a portion thereof. Theconnector or port may be, at least in part, separate from, but operablycoupled to, the upper flange portion or the lower portion. For example,the connector or port may be operably coupled to the first or secondopenings of the upper flange portion or the lower portion to place theconnector or port in communication with the fluid flow path.

The implantable cranial medical device may comprise one or more braincatheter connectors. For purposes of the present disclosure, a “braincatheter connector” is a connector operably couplable to a catheter thatis configured to extend from the implantable cranial medical device intoa brain of a subject, such as into a CSF-containing space (e.g., acerebral ventricle), when implanted in the subject.

A brain catheter connector of the implantable cranial medical device maybe coupled to a brain catheter in any suitable manner. For example, thebrain catheter and the brain catheter connector may comprisequick-release couplings, luer lock fittings, snap connect couplings, orthe like. In some examples, the brain catheter is configured to becoupled to the brain catheter connector via interference fit. The braincatheter connector may comprise a fitting, which may comprise externalbarbs, configured to be inserted into a lumen of the brain catheter toretain the brain catheter relative to the brain catheter connector andto place the lumen of the brain catheter in fluid communication with thefluid flow path of the implantable cranial medical device.

In some embodiments, the brain catheter connector comprises a firstportion of a compression fitting and a second portion of the compressionfitting is placed over the catheter. Connecting the first and secondportion of the compression fitting may compress the external catheter tosecure the catheter to the external catheter connector. For example, thecompression fitting may cause the catheter to compress against externalbarbs. The second portion of the compression fitting may comprise acompression ferrule and a connection element to connect to the firstportion of the fitting on the external catheter connector.

A brain catheter connector may be positioned at any suitable location ofthe implantable cranial medical device. Preferably, the brain catheterconnector is located at a bottom of the device, such as at a bottom ofthe lower portion of the housing. For example, the brain catheterconnector may extend from a bottom major surface of the lower portion ofthe housing. While the bottom major surface of the lower portionpreferably does not extend beyond the bottom of a burr hole in which isplaced, the brain catheter connector may extend beyond the bottom of theburr hole.

Preferably, the brain catheter connector comprises a first lumen incommunication with the first fluid path of the device and comprises asecond lumen in communication with the second fluid path of the device.Preferably, such a catheter connector is configured to connect with adual lumen brain catheter. Upon coupling the dual lumen brain catheterto the brain catheter connector, a first lumen of the brain catheter maybe placed in fluid communication with the first lumen of the braincatheter connector, and a second lumen of the brain catheter may beplaced in fluid communication with the second lumen of the braincatheter connector. The lumens of the brain catheter may be used tocarry fluid to or from one or more regions of the central nervoussystem. Preferably, at least one lumen of the brain catheter is inplaced in fluid communication with a CSF-containing space. CSF exits theforamen of Magendie and Luschka to flow around the brainstem andcerebellum. CSF flows within the subarachnoid space. CSF is produced inthe ventricular system of the brain and communicates freely with thesubarachnoid space via the foramen of Magendie and Luschka. The lumen ofthe brain catheter may be placed in communication with CSF anywhere thatthe CSF is accessible. For example, the lumen may be placed incommunication with an intrathecal space, a cisterna magna, asubarachnoid space or a cerebral ventricle. Preferably, the lumen isplaced in communication with a cerebral ventricle. Preferably, thecerebral ventricle is a lateral cerebral ventricle.

Preferably, the brain catheter is operably coupled to the brain catheterconnector before the brain catheter is implanted. In some embodiments,the brain catheter is connected to the brain catheter connector by amanufacturer. A brain catheter may be permanently or reversibly coupledto the brain catheter connector.

A brain catheter may have any suitable length. Preferably, the braincatheter has a length sufficient to extend to a CSF-containing space,such as a cerebral ventricle, when coupled to the cranial medical devicewhen implanted. In some embodiments, the brain catheter has a lengthfrom about 55 millimeters to about 80 millimeters, such as from about 60millimeters to about 70 millimeters, or from about 62 millimeters toabout 68 millimeters. Such lengths may be suitable for the braincatheter to extend to a lateral cerebral ventricle.

The brain catheter may have any suitable outer diameter. Preferably, theouter diameter is from about 2 mm to about 4 mm, such as from about 2 mmto about 3 mm, or from about 2 mm to about 2.5 mm.

Preferably, the brain catheter comprises two lumens. The two lumens maybe oriented in any suitable manner. For example, the two lumens may beconcentric, such as a lumen within a lumen (or catheter within acatheter) or may be side-by-side. Preferably, the outer surface of thebrain catheter has a substantially circular cross-sectional shape.

The brain catheter may comprise an inner wall running along the lengthof the catheter. The inner wall may separate the two lumens of the braincatheter. The brain catheter may comprise two semicircular (or D-shaped)cross-sectional shaped lumens running along the length of the catheter.The semicircular lumens may be of any suitable size. For example, theinner dimension of the semicircular lumens at their largest width may bein a range from about 0.9 millimeters to about 1.5 millimeters, such asfrom about 1.1 millimeters to about 1.5 millimeters, or from about 1.2millimeters to about 1.4 millimeters. The inner dimension of thesemicircular lumens at their smallest width may be in a range from about0.4 millimeters to about 0.7 millimeters, such as from about 0.5millimeters to about .6 millimeters, or from about 0.55 millimeters toabout 0.6 millimeters. The inner dimensions of the first and secondlumens may be the same or different. Preferably, the inner diameter ofthe first and second lumen are the same or substantially the same (e.g.,do not vary by more than 10%).

The brain catheter may comprise any suitable material. The material ispreferably biocompatible and compatible with a therapeutic fluid thatmay be delivered through a lumen of the catheter. The material ispreferably biocompatible and compatible with CSF that may be flowthrough a lumen of the catheter. Preferably, the material is biodurable.A biodurable material is a material that is compositionally andstructurally stable for extended periods of time in a biologicalenvironment. Products made from such materials should not exhibitsubstantial breakdown, degradation, erosion, or deterioration ofmechanical properties relevant to their employment when exposed tobiological environments for periods of time commensurate with the use ofthe implantable device. An intended biological environment can beunderstood to be in vivo, i.e. associated with an implantable device ina patient. The period of implantation of a brain catheter describedherein may be weeks, months, or years. For example, a brain catheter maybe made from materials that are biodurable for at least 29 days, such asat least one year, at least three years, or at least five years.

Any suitable homopolymer, copolymer, blends of polymers or combinationsof polymers may be used to form the brain catheter. Preferably, thepolymers used to make the catheters are flexible during both fabricationand assembly. Preferably, the catheters are formed from materials thatresult in a flexible and soft catheter during its in vivo implantationperiod.

Preferably, the chemical composition and molecular structure is selectedso that the catheter materials are flexible and soft but still remainbiodurable and resist substantial breakdown, degradation, erosion, ordeterioration of mechanical properties when exposed to therapeuticagents or excipients delivered over extended periods of time.Flexibility and softness are characteristics that tend to cause acatheter to lack biodurability and long-term compatibility in oxidative,hydrolytic, and body fluid contact environments. Accordingly, the choiceof polymers should be carefully selected to achieve sufficientcompatibility with the therapeutic agent and excipients, biodurability,flexibility, and softness.

Depending on compatibility with the therapeutic agent and excipients tobe employed, the brain catheter may comprise cross-linked silicone,which may form flexible catheters. The glass transition temperature ofcross-linked silicone may depend on the cross-link density. In someembodiments, the brain catheter may comprise cross-linked siliconehaving a Tg below -40° C., such as below -90° C. In some instances,components of therapeutic fluids may interact with a cross-linkedsilicone catheter. In some instances, components of therapeutic fluidsmay leach or extract components or parts of a cross-linked siliconecatheter. Swelling and leaching or extraction may affect the biodurablenature of soft and flexible cross-linked silicone and its capability tomaintain dimensions or wall thickness and structure to provide multiplestable fluid paths over extended periods of time.

In some embodiments, a brain catheter comprises polyurethane.Preferably, the brain catheter comprising polyurethane resistsdegradation in oxidative, hydrolytic, and body fluid contactenvironments. The polyurethane may comprise biostable hard and softsegments. The polyurethane may comprise a higher hard segment content.Such polyurethanes may resist degradation in oxidative, hydrolytic, andenzymatic changes under physiological conditions and body fluid contact.In some embodiments, the brain catheter comprises a polyurethanecontaining hard and soft segments that are formed by reacting a diol orpolyol (an alcohol with more than two reactive hydroxyl groups permolecule) with a diisocyanate or a polymeric isocyanate in the presenceof suitable catalysts and additives. The isocyanates (sometime chainextended with diols) form the hard segments and the polyols form thesoft segments, with the segments linked by the urethane bonds formedfrom the reaction between the polyols and diisocyanate.

In some embodiments, the hard segment of the polyurethane comprises ofan aromatic isocyanate. In some embodiment, the hard segment of thepolyurethane comprises an aliphatic isocyanate. Preferably, the hardsegment comprises an aromatic isocyanate as.

In some embodiments, the soft segment of the polyurethane comprises of apolyether. In some embodiments, the soft segment of the polyurethanecomprises of a polycarbonate. The soft segment may provide suitableflexibility for use in single lumen catheters and multi-lumen catheters.

In some embodiments, a brain catheter comprises a polyurethane that issemi-crystalline with higher hardness. The semi-crystalline nature ofthe polyurethane polymers makes them resistant to swelling and leachingwhen in contact with CSF, therapeutic fluids, and therapeutic fluidshaving high concentration therapeutic agents. Semi-crystallinepolyurethanes may be resistant to degradation in oxidative, hydrolytic,and enzymatic changes and body fluid contact environments. Higherhardness may provide a polyurethane resistant to swelling and leachingwhen in contact with CSF, therapeutic agents, and highly concentratedtherapeutic agents. Higher hardness polyurethanes may be resistant todegradation in oxidative, hydrolytic, and enzymatic changes and bodyfluid contact environments. A polyurethane with a higher hardness (i.e.higher A or preferably D hardness scale) may have less soft segment andhigher crystallinity, which may slow diffusion and interaction withsolvents and solutions. Accordingly, brain catheters comprisingpolyurethane may be less susceptible to swelling or attack by solventsand solutions of therapeutic fluids.

A brain catheter comprising a polyurethane with higher hardness mayallow for reduced wall thickness and may provide for processingadvantages for single lumen brain catheters and multi-lumen braincatheters.

In some embodiments, the catheter may be formed from a material having aShore A hardness in a range from about 70A to about 110A. In someembodiments, the catheter may be formed from a material having a Shore Ahardness above 80A or preferably above 90A. In some embodiments, thecatheter is formed from a material having a Shore D hardness of about30D to about 70D, such as from about 40D to about 60D, or from about 50Dto about 60D.

The brain catheter may comprise a semicrystalline polymers other than apolyurethane. The semicrystalline polymers may be selected to provideresistance to degradation in oxidative, hydrolytic, and enzymaticchanges and body fluid contact environments while maintaining thedesired flexibility through thinner wall or lower wall thickness. Insome embodiments, a brain catheter comprises one or more of polyolefin,polyethylene, a fluorinated polymer, a fluorinated homopolymer, afluorinated copolymer, a homopolymer of polyvinylidene difluoride(PVDF), a copolymer of PVDF, a copolymer of tetrafluoroethylene (TFE)and hexafluoro propylene (HFP), and polychlorotrifluoroethylene. Apolyolefin may provide resistance to change during its in vivo lifethrough its high crystallinity and long hydro-carbon chains, and afluorinated polymer may provide resistance to change during its in vivolife through its high crystallinity and the inert nature of fluorine.

Some examples, of polymers that may be used to form a brain catheter asdescribed herein include aliphatic or aromatic, polycarbonate-basedthermoplastic polyurethane, such as CARBOTHANE (available from Lubrizol,Wickliffe, Ohio, USA), perfluoroelastomers, such as KALREZ (availablefrom DuPont, Wilmington, Delaware, USA); PVDF, such as KYNAR FLEX(available from Daikin, Osaka, Japan) or KYNAR ULTRAFLEX (available fromArkema, Colombes, France); fluorinated ethylene propylenes, such asNEOFLON (available from Daikin, Osaka, Japan).

It should be understood that identifying a polymer or polymers thatprovide resistance to substantial breakdown, degradation, erosion, ordeterioration of mechanical properties but at the same time is flexiblewhile maintaining catheter dimensions, wall thickness, and structure isnot trivial, in particular if the catheter is intended for implanted useover extended periods of time. In addition, it should be understood thatthe design challenges associated in identifying a suitable polymer orpolymers for forming the catheters in combination with design concernsassociated with the implantable cranial medical device, some of whichare described above, present substantial challenges. Accordingly, thedesign of a suitable implantable cranial medical device as describedherein with a suitable brain catheter was not a trivial task.

In some embodiments multiple single lumen brain catheters are made fromthe same polymer or polymers. In other embodiments, the multiple singlelumen brain catheters are made from different polymers. In someembodiments, multiple single lumen brain catheters are separated fromeach other. In other embodiments, the two single lumen brain cathetersare bonded to each other, such as via chemical bonding or thermalbonding. In some embodiments, more than one lumen of a multi-lumen braincatheter is made from the same polymer or polymers. In otherembodiments, lumens of a multi-lumen lumen brain catheter are made fromdifferent polymers. In some embodiment, all lumens of a multi-lumenbrain catheter are made from the same polymer or polymers. In otherembodiments, two or more lumens of a multi-lumen brain catheter are madefrom two or more different polymers.

Exterior surfaces of the brain catheter preferably comprise materialthat are biocompatible. Preferably, exterior surfaces of the braincatheter inhibit tissue adhesion. Preferably, exterior surfaces of thebrain catheter are easily inserted. A hydrophilic coating, such as ahydrogel, may be applied to an exterior surface to cause the exteriorsurface to be lubricious to facilitate insertion of the catheter intothe brain. The exterior surface of the catheter may be coated withpolytetrafluorethylene (PTFE) or another polymer to improveinsertability, decrease adhesion, or increase insertability and decreaseadhesion. In some embodiments, the structural material of the catheteris sufficiently insertable and sufficiently resists tissue adhesionwithout an additional coating. If a coating is applied, the surface ofthe catheter preferably includes functional groups that may covalentlybind with a coating. The surface of the catheter may be treated tointroduce functional groups, or the functional groups may be present inthe material forming the catheter.

The brain catheter may include or may be coated with an antimicrobialmaterial, such as antimicrobial silver or an antibiotic. In someembodiments the brain catheter includes or is coated with a compositioncomprising a combination of minocycline and rifampin. In someembodiments, the brain catheter is soaked in a solution comprising anantimicrobial agent, and the antimicrobial agent is taken up by thematerial forming the brain catheter.

The brain catheter may comprise radiopaque material visible by imaging,such as X-ray or magnetic resonance imaging (MRI). The brain cathetermay comprise radiopaque material throughout the catheter, may comprise aconcentrated area of radiopaque material, or may comprise radiopaquematerial throughout the catheter and may comprise a concentrated area ofradiopaque material. The brain catheter may comprise a concentratedradiopaque material at the distal end portion. The brain catheter maycomprise one or more concentrated radiopaque bands or markings along thelength of the marker that may be used to determine the depth of thecatheter during or after implantation.

The brain catheter may comprise any suitable radiopaque material.Examples of suitable radiopaque material includes barium sulfate,tantalum, and titanium.

In some embodiments, barium sulfate is blended with the polymer formingthe catheter such that the barium sulfate is distributed through thecatheter. Any suitable concentration of barium sulfate may be used. Insome examples, about 5% barium sulfate by weight to about 20% bariumsulfate by weight is blended into the polymer forming the catheter. Forexample, about 10% barium sulfate by weight to about 15% barium sulfateby weight, or about 12% barium sulfate may be blended into the polymerforming the catheter. 12% barium sulfate blended into the polymer wasempirically determined to provide a suitable balance of a number offactors, including (i) ability to visualize the catheter throughout theimplant process as it penetrates, (ii) manufacturability of thin-walleddual lumen catheter, and (iii) compatibility with fluids comprising highconcentration therapeutic agents that may be infused through thecatheter. Balancing these factors may achieve biocompatibility andbiostability for the life of its implant, such as 5 years or more. Insome embodiments, a tantalum marker, such as a tantalum bead, ispositioned in the brain catheter at the distal end portion.

The brain catheter may comprise one or more openings in communicationwith a lumen of the catheter through which fluid may flow. The braincatheter may comprise any suitable number of openings in communicationwith each lumen. For example, the brain catheter may comprise one to tenor more openings in communication with each lumen, such as two to sixopenings or three to four openings in communication with each lumen. Thebrain catheter may have the same number of openings in communicationwith the first lumen as in communication with the second lumen. Thebrain catheter may have a different number of openings in communicationwith the first lumen than in communication with the second lumen.

The openings may be of any suitable size and may be configured in anysuitable manner. The openings have a diameter or width of from about 0.2millimeters to about 1 millimeter, such as from about 0.4 millimeters toabout 0.6 millimeters, or about 0.5 millimeters. The openings may havethe same or different diameters or widths.

The openings may be any suitable shape. For example, the openings mayhave circular or elliptical cross-sectional shapes, rectangularcross-sectional shape, triangular cross-sectional shape, or the like, orcombinations thereof.

The openings may be always be open or may be configured to open due to apressure differential in the lumen of the catheter and CSF in which thedistal end portion of the brain catheter is implanted. For example, theopenings may comprise slits that open due to relative positive pressurein the lumen when fluid is infused through the lumen to the CSF or dueto relative negative pressure in the lumen when CSF is aspirated throughthe lumen. The slit may be cut into a resilient material that flexeswhen under pressure but returns to an original shape as pressureequalizes.

The openings may be positioned at any suitable location of the catheter.In some embodiments, the one or more openings of the brain catheter incommunication a lumen configured to infuse therapeutic fluid (e.g., thelumen in communication with the second fluid path of the implantablecranial medical device) may be positioned a short distance from thedistal tip of the brain catheter. The one or more openings of the braincatheter in communication with a lumen through which CSF is configuredto be aspirated (e.g., the lumen in communication with the first fluidpath of the implantable cranial medical device) may be positioned at orin proximity to the distal tip. Separating infusion openings fromaspiration openings may allow for infused fluid to mix with CSF so thataspirated CSF better represents concentrations of therapeutic agent inCSF than if the infusion and aspiration openings were in proximity toeach other. If the infusion and aspiration openings are located adjacentto one another, then aspirated CSF may have higher concentration thatCSF at a location more remote from the aspiration lumen. If theaspiration and infusion openings are located further apart from oneanother, then the aspirated fluid would be more representative of theentire CSF.

In addition to positioning aspiration and infusion openingslongitudinally apart (closer to or further from the distal tip), theaspiration openings and the infusion openings may be placed on generallyopposing sides of the brain catheter. For example, the aspirationopenings and the infusion openings may be positioned from about 160degrees to about 180 degrees radially apart from one another. Bypositioning the infusion ad aspiration lumens radially apart,substantial mixing of CSF with therapeutic fluid infused through aninfusion opening may occur prior to aspirating the CSF through anaspiration opening.

In addition to positioning aspiration and infusion openings away fromeach other in a staggered manner in the cerebral ventricle, the positionof the openings may be substantially separated such that the infusionholes are placed within a tissue location in the brain other than thecerebral ventricle but the aspiration openings remain in the CSF.

The lumens of the brain catheter may have the same or different lengths.The lumens of the brain catheter may have a length that extends from aproximal end portion, which may be coupled to the brain catheterconnector of the implantable cranial medical device, to the distal-mostopening in the catheter in communication with the respective lumen. Ifthe lumens of the brain catheter are configured to carry fluid to orfrom the same brain location, such as a cerebral ventricle, the lumensmay have the same or substantially similar lengths. If the lumens of thebrain catheter are configured to carry fluid to or from different brainlocations, such as a ventricle and brain parenchyma, the lumens may beof substantially different lengths. For purposes of the presentdisclosure, lumens having “substantially different” lengths are lumensthat have lengths that differ by more than 10 percent. Lumens that have“substantially similar” lengths are lumens that have lengths that differby 10 percent or less.

In some embodiments, the brain catheter comprises multiple infusionopenings positioned a distance from the distal tip, such as from about 3millimeters from the distal tip to about 15 millimeters from the distaldip. For example, all the infusion openings may be positioned from about3 millimeters to about 10 millimeters from the distal dip, or from about4 millimeters to about 8 millimeters from the distal tip. In someembodiments, at least one aspiration lumen is positioned at the distaltip of the brain catheter.

In some embodiments, the implantable cranial medical device comprises acatheter connector configured to connect to an external catheter. Forpurposes of the present disclosure, an “external catheter” is a catheterthat may be coupled to a device separate from the implantable cranialmedical device or may serve as a CSF shunt or drainage catheter. The“external catheter” may be completely implanted in a subject when in useor may be partially implanted and partially external to the subject whenin use. The separate device may be, for example, an infusion device. Theinfusion device may be implantable or non-implantable. Thenon-implantable infusion device may be an ambulatory device or astationary device. The infusion device may be manually powered,electromechanically powered, chemically powered, or otherwise powered.In some examples, the infusion device may comprise a piston pump, aperistaltic pump, an osmotic pump, a plunger, or the like. A distalportion of the CSF shunt or drainage catheter may be placed in anysuitable location of the patient, such as the peritoneal cavity.

The external catheter connector of the implantable cranial medicaldevice may be coupled to the catheter in any suitable manner. Forexample, the external catheter and the external catheter connector maycomprise quick-release couplings, luer lock fittings, snap connectcouplings, or the like. In some examples, the external catheter isconfigured to be coupled to the external catheter connector viainterference fit. The external catheter connector may comprise afitting, which may comprise external barbs, configured to be insertedinto a lumen of the external catheter to retain the external catheterrelative to the external catheter connector and to place the lumen ofthe external catheter in fluid communication with the fluid flow path ofthe implantable cranial medical device.

In some embodiments, the external catheter connector comprises a firstportion of a compression fitting and a second portion of the compressionfitting is placed over the catheter. Connecting the first and secondportion of the compression fitting may compress the external catheter tosecure the catheter to the external catheter connector. For example, thecompression fitting may cause the catheter to compress against externalbarbs. The second portion of the compression fitting may comprise acompression ferrule and a connection element to connect to the firstportion of the fitting on the external catheter connector.

The catheter connector may be configured to securely engage any suitablecatheter. In some embodiments, the external catheter connector isconfigured to couple to a catheter having an inner diameter from about0.4 millimeters to about 1 millimeter, such as about 0.5 millimeters toabout 0.7 millimeters, or about millimeters.

The external catheter connector may be positioned at any suitablelocation of the implantable cranial medical device. Preferably, theexternal catheter connector is located at a portion of the device thatis implanted between the skull and the scalp. For example, the externalcatheter connector may be formed from, operably coupled to, or formedfrom and operably coupled to an opening in the upper flange portion.

The external catheter connector may be oriented in any suitable manner.For example, the external catheter connector may have a longitudinalaxis that extends substantially parallel to a bottom surface of theupper flange portion. For purposes of the present disclosure, alongitudinal axis that extends “substantially” parallel to a surface isa longitudinal axis that does not vary from parallel by more than 10degrees. As another example, the housing, when defining an exteriorsurface of the upper flange portion and the lower portion, may comprisea central axis that extends through the lower portion and the upperflange portion, and the external catheter connector may have alongitudinal axis that extends substantially orthogonal to the centralaxis. For purposes of the present disclosure, a longitudinal axis thatextends “substantially” orthogonal to another axis is a longitudinalaxis that does not vary from orthogonal by more than 10 degrees.Preferably, the external catheter connector extends substantiallyparallel to the skull of the patient. Such an orientation may permit thecatheter to readily run along a surface of the skull in proximity to theimplantable cranial medical device.

In some embodiments, the implantable cranial medical device comprises aport defining an opening in communication with a fluid flow path of theimplantable cranial medical device. The port is preferably configured toreceive a needle through which fluid may be infused into, or withdrawnfrom, the fluid path of the device. Preferably, the port is positionedand oriented to allow the needle to access the port through the scalp ofthe subject in which the device is implanted. For example, the port maybe defined by, or operably coupled to, a top surface of the device, suchas the top surface of the upper flange portion of the housing.Preferably, the port is substantially aligned with the center of the topsurface of the upper flange portion of the housing.

The port may comprise a ferrule or funnel that decreases in innerdiameter from a location in proximity to the top surface of the deviceto an interior portion of the device to facilitate alignment with theneedle inserted in the port with a portion of the fluid flow path. Theferrule or funnel may also limit insertion of the needle beyond a bottomof the ferrule or funnel. The ferrule or funnel may be formed from anysuitable material, such as a metallic material, a ceramic material, aglass material, or a hard plastic material, or combinations thereof.

The port may comprise a sealing element, such an O-ring, to seal theneedle relative to the port and to place a lumen of the needle in sealedcommunication with the fluid flow path of the implantable cranialmedical device.

A septum may be disposed across the opening of the port. Preferably, theseptum may be a self-sealing septum. A self-sealing septum may allowmultiple cycles of needle insertion into and withdrawal from the portwhile continuing to seal the port from an interstitial environment inwhich the port may be located when implanted. The implantable cranialmedical device may comprise any suitable self-sealing septum. Forexample, the self-sealing septum may comprise silicone, a polyethylene,of the like, and combinations thereof.

The port may be configured to receive a needle of any suitable gauge.The needle may be inserted through the septum to infuse fluid throughthe first fluid flow path and first lumen of a catheter communicationwith the first fluid flow path or to aspirate fluid from the subj ectthrough the first lumen and first fluid flow path. The tapered nature ofthe ferrule or funnel may accommodate needles of a variety of sizes. Forexample, the ferrule or funnel may accommodate needles with a range ofsizes from about 16 gauge to about 25 gauge, such as from about 18 gaugeto about 22 gauge. The gauge of needle employed may vary depending onthe material introduced or withdrawn from the port. For example, asmaller gauge needle may be more desirable for more viscous fluids offluids containing larger molecules or particles, such as cells orproteins.

Preferably, port is configured to receive non-coring needles, such asHuber needles or butterfly needles. Non-coring needles may be designedwith a deflected or offset ‘B’ bevel point. Such a tip has the advantageof parting rather than cutting a plug from or coring the septum of theport and may create a more comfortable injection. Using a non-coringneedle, such as a Huber needle, may preserve the integrity of the septumand may prevent a plug of septum material from being cut and passed intothe CSF.

In some embodiments, a kit may include one or more non-coring needles.

The ferrule or funnel may have an inner surface defining a reservoir.The reservoir may have any suitable volume. For example, the reservoirmay have a volume suitable to receive a non-coring needle. In someembodiments, the reservoir has a volume within a range from about 2milliliters to about 7 milliliters, such as from about 3 milliliters toabout 5 milliliters.

Reference is now made to FIGS. 1-3 , which illustrate an example of anembodiment of an implantable cranial medical device 100 of the presentdisclosure. The implantable cranial medical device 100 comprises anupper flange portion 110 and a lower portion 120. The upper flangeportion has a generally convex top surface 112 and a generally flatbottom surface 114. The upper flange portion 110 is configured to bepositioned between a skull and a scalp of a subject when implanted, withthe bottom surface 114 configured to rest on a skull of a subject. Theupper flange portion 110 has a height H_u and a width W_u. The heightH_u of the upper flange portion 114 is sufficiently small to avoid skinerosion and substantial discomfort to the subject when implanted. Thewidth W_u of the upper flange portion 114 is sufficiently large to reston the skull around a burr hole.

The lower portion 120 has a bottom surface 124, a height H_1 and a widthW_1. The height H_1 of the lower portion 120 is sufficiently small sothat the bottom major surface 124 of the lower portion 120 does notextend substantially below the burr hole when implanted in a subject.Preferably, the bottom major surface 124 of lower portion 120 does notextend below the burr hole when implanted in a subject. The width W_1 ofthe lower portion 120 is sufficiently small such that the lower portion120 fits within the burr hole when implanted.

The upper flange portion 110 defines a first opening 116 and a secondopening 118. The lower portion 120 defines a first opening 126 and asecond opening 128. A first fluid flow path (not shown in FIGS. 1-3 )extends within a housing 101 from the first opening 116 of the upperflange portion 110 to the first opening 126 of the lower portion 120. Asecond fluid flow path (not shown in FIGS. 1-3 ) extends within thehousing 101 from the second opening 118 of the upper flange portion 110to the second opening 128 of the lower portion 120.

Reference is now made to FIGS. 4-7 in which an embodiment of animplantable cranial medical device 100 is shown. As with the embodimentshown in FIGS. 1-3 , the embodiment of an implantable cranial medicaldevice 100 shown in FIGS. 4-7 includes an upper flange portion 110having a top surface 112 and a bottom surface 114 and includes a lowerportion 120 having a bottom major surface 124. Fastener feedthroughs 160extend through the upper flange portion 110 from the top surface 112 tothe bottom surface 114 and are configured to receive fasteners 162, suchas screws, which may be used to anchor the housing to the skull of asubject in which the device 100 is implanted.

The device 100 includes a port 150 in communication with the first fluidpath 192. The lateral edge of the port 150 is defined by the firstopening 116 defined by the top surface 112 of the upper flange portion110. A self-sealing septum 170 extends across the opening 116. When thedevice 100 is implanted, the port 150 is positioned and oriented toreceive a needle inserted through the scalp such that a lumen of theneedle is placed in fluid communication with the first fluid path 192.

The device 100 includes a reservoir 180 in communication with andforming a part of the first fluid path 192. The reservoir 180 ispositioned such that insertion of a needle into the port 150 places alumen of the needle in fluid communication with the reservoir 180. Thereservoir 180 is disposed with the housing 101 and may form a part ofthe first fluid flow path 192.

The device also includes an external catheter connector 140 that extendssubstantially parallel with the bottom surface 114 of the upper flangeportion 110 of the device 100. The external catheter connector 140 isoperably coupled to an opening defined by the upper flange portion 110(such as second opening 118 depicted in FIG. 1 ). The external catheterconnector 140 defines a passageway in communication with the secondfluid path 194 of the device 100. The external catheter connector 140 isconfigured to operably couple to an external catheter to place a lumenof the external catheter in fluid communication with the second fluidpath 194. The external catheter may further be coupled to a device otherthan the implantable cranial infusion device, such as an infusiondevice. The infusion device may implantable or non-implantable.

The implantable cranial medical device 100 also includes a braincatheter connector 130 having a first lumen 132 and a second lumen 134.The brain catheter connector 130 extends from the bottom major surface124 of the lower portion of the housing 120. The first lumen 132 of thebrain catheter connector 130 is operably coupled to the first fluid path192. The second lumen 134 of the brain catheter connector 130 isoperably coupled to the second fluid path 194. The brain catheterconnector 130 is configured to operably couple to a dual lumen catheter,which may have a distal end. The distal end may be implantable in aCSF-containing space, such as a cerebral ventricle.

As shown in FIG. 7 , the brain catheter connector 130 may include a slot135 configured to receive a portion of a catheter that separates onelumen from another in a dual catheter. For example and with reference toFIG. 8 , a central portion 215 of a body 210 of a brain catheter 200that separates a first lumen 212 from a second lumen 214 may be insertedinto slot 135 of the brain catheter connector 130 such that the firstlumen 212 of the catheter 200 is placed in fluid communication with thefirst lumen 132 of the brain catheter connector 130 and such that thesecond lumen 214 of the catheter 200 is placed in fluid communicationwith the second lumen 134 of the brain catheter connector 130.

Referring now to FIGS. 9 and 10 , distal portions 202 of embodiments ofbrain catheters are shown. The brain catheter includes a first lumen 212and a second lumen 214 separated by a central wall 215 of the body 210of the catheter. The first lumen 212 is in communication with one ormore openings 222 at the distal end portion 202. In the depictedembodiment, the first lumen 212 is in communication with three sideopenings 222B at the distal end portion 202 and a distal end opening222A. The second lumen 214 is in communication with one or more sideopenings 224 at the distal end portion 202. In the depicted embodiment,the second lumen 212 is in communication with four side openings 224 atthe distal end portion 202. The side openings 222A and 224 arepositioned on generally opposing sides of the catheter. The distance(D1) from the distal tip to the side opening 222A furthest from thedistal tip is less than the distance (D2) from the distal tip to theside opening 224 furthest from the distal tip. Preferably, all theopenings 224 in communication with the second lumen 214 are positionedaway from the distal tip a distance greater than D1. The position andorientation of the openings 222A, 222B, 224 allow for therapeutic fluidthat may be infused through the second lumen through side openings 224to substantially mix with CSF prior to being aspirated through openings222A, 222B and through the first lumen 215.

In the embodiment depicted in FIG. 10 , D2 is substantially greater thanD1. Accordingly, the catheter depicted in FIG. 10 may be suitable fordelivering fluid to, or withdrawing fluid from, for example, a cerebralventricle through openings 222A and 222B and may be suitable fordelivering fluid to brain parenchyma through openings 224.

In the embodiment depicted in FIG. 9 , the difference between D2 and D1is not as larger as depicted in FIG. 10 . Accordingly, the catheterdepicted in FIG. 9 may be suitable for delivering fluid to, orwithdrawing fluid from, for example, a cerebral ventricle throughopenings 222A and 222B and through openings 224.

In the embodiment depicted in FIGS. 9 and 10 , the catheter includes aradiopaque marker 230 visible by X-ray, magnetic resonance imaging(MRI), or X-ray and MRI imaging so that the location of the distal endportion 202 may be readily determined. The depicted radiopaque marker230 comprises tantalum and is embedded in the distal end of thecatheter. The body 210 may comprise barium sulfate or another radiopaquematerial (not shown) dispersed throughout. In some embodiments (notshown), the brain catheter may include radiopaque markers at locationsalong the length of the catheter to form depth markings that may be usedto determine the depth of the catheter during or after implantation.

Referring now to FIG. 11 , components of an external catheter connector140 and a port 150 associated with an upper flange portion 110 of animplantable cranial medical device 100 are shown. The outer edge of theport 150 is defined by a first opening 116 defined by a top surface 112of the upper flange portion 110. The port 150 includes a septum 170 orcap, a compression wedge 152, and an axial ferrule 715, which defines adecreasing inner diameter moving in a direction from the top surface 112of the upper flange portion 110 towards the bottom surface of the upperflange portion 110. The axial ferrule 715 serves to guide a needleinserted into the port 150 into a position suitable for placing a lumenof the needle in fluid communication with the first fluid path of thedevice 100. The axial ferrule 715 may also limit insertion of the needlebeyond a bottom end of the ferrule 715.

The external catheter connector 140 includes a compression fitting, suchas sleeve 144, defining a lumen configured to receive an externalcatheter and a barbed fitting 142 configured to be inserted into a lumenof the external catheter. The barbed fitting 142 includes a passagewayin communication with the second fluid path of the device 100. Thecompression sleeve 144 may be disposed about the external catheter andslid towards the end of the catheter after the catheter has beenadvanced over the barbed fitting 142 to cause the external catheter tobe compressed against the barbed fitting 144.

Referring now to FIG. 12 , a photograph of a cut-away of a housing 101of an embodiment of implantable cranial medical device is shown. Thehousing 101 defines the upper flange portion 110, the lower flangeportion 120, the external catheter connector 140, the brain catheterconnector 130, the first fluid path 192, and the second fluid path 194.The housing 101 also defines an opening 199 configured to components ofa port, such as a septum and reservoir to guide a needle in positionrelative to the first fluid flow path 192. The depicted housing 101 isformed from titanium but may be formed from any suitable material.

Kit

The implantable cranial medical device described herein may be includedin a kit. The kit may include a brain catheter. The brain catheter maybe coupled to the implantable cranial medical device in the kit or maybe coupled by an end user, such as a healthcare professional.Preferably, the brain catheter is coupled to the implantable cranialmedical device prior to packing in the kit. The kit may include acompression fitting to aid in connecting an external catheter to anexternal catheter connector of the implantable cranial medical device.The kit may include fasteners, such as screws, configured to secure theupper flange portion of the implantable cranial medical device to theskull of a subject. The kit may include a tool, such as a screwdriver,for use with the fasteners. The kit may include a needle configured toaccess a port of the implantable cranial medical device, which may beused for, for example, aspiration. The needle may be a non-coringneedle, such as a Huber needle or a butterfly needle.

While only a few kit components are listed above, it will be understoodthat any component discussed herein may be included in a kit comprisingan implantable cranial medical device.

Implantation

The implantable cranial medical devices and associated devices describedherein may be implanted in any suitable manner. In some embodiments, abrain catheter having a distal end and a proximal end is implanted suchthat the distal end is positioned in a CFS-containing region, such as acerebral ventricle, of a subject. The proximal end may be positioned inproximity to a burr hole in a skull. Preferably, the brain catheter is adual lumen catheter. The proximal end of the catheter may be coupled tothe implantable cranial infusion device to place one lumen of the braincatheter in communication with the first fluid path of the implantablecranial medical device and the second lumen of the brain catheter incommunication with the second fluid path of the implantable cranialmedical device. The implantable cranial infusion device may be implantedsuch that the lower portion is disposed in the burr hole and the upperflange portion is between a skull and a scalp of a subject. The upperflange portion may be secured to the skull via one or more fasteners,such as screws.

The brain catheter may be coupled to the implantable infusion devicebefore or after the distal end of the brain catheter is positioned inthe cerebral ventricle. Preferably, the brain catheter is coupled to theimplantable cranial medical device prior to the brain catheter beingimplanted. A stylet may be inserted through a fluid flow path, such asthe first fluid flow path, of the implantable cranial medical device andinto a lumen, such as the first lumen, of the brain catheter tofacilitate implanting the catheter into the brain of a subject. Forexample, the stylet may be inserted through a septum of a port incommunication with the first fluid path, through the first fluid path,and into the first lumen.

A subject, in which the implantable cranial medical device andassociated components may be implanted, may undergo a preoperative scanfor surgical planning. A surgical navigation system may be employedduring an implant procedure to facilitate placement of the braincatheter. The brain catheter may be radiopaque, may include one or moreradiopaque markers, or may be radiopaque and include one or moreradiopaque markers to allow visualization with the surgical navigationsystem employed. For example, Medtronic, Inc.’s AxiEM™ electromagnetictechnology and StealthStation® Navigation System and B. Braun Aesculapdivision’s Intraventricular Disposable Introducer Set™ may be used tofacilitate implantation of the catheter. Preferably, the distal endportion of the catheter is positioned in a cerebral ventricle of thesubject. Preferably, the distal end portion of the catheter ispositioned in a lateral ventricle. However, the distal end portion ofthe brain catheter may be placed in any suitable location, such in thecisterna magna, a subarachnoid space, or the like.

Referring now to FIG. 13 , an example illustrating an implantablecranial medical device 100 and coupled brain catheter 200 is show. Thedevice 100 and brain catheter 200 are shown prior to the catheter 200being implanted. As shown in FIG. 13 , a stylet 300 may be inserted intothe port 150 of the implantable cranial medical device 100, through thefirst fluid path (such as fluid path 192 shown in FIG. 6 ) and at leastpartially through a first lumen (such as lumen 212 shown in FIG. 8 ) tofacilitate implanting the distal end 202 of the catheter 202 in acerebral ventricle of a subject. The brain catheter 200 is typicallyflexible and lacks rigidity. The stylet 300 may provide structuralrigidity to allow insertion of the distal end 202 of the catheter 200through brain tissue and into the cerebral ventricle.

For example, and as shown in FIG. 14 , the distal end portion 202 of thebrain catheter 200 may be implanted in a lateral ventricle 400 of abrain 500 of a subject. The proximal end of the brain catheter 200 maybe coupled to a brain catheter connector (not shown) of the device 100.The lower portion 120 of the implantable cranial medical device 100 maybe positioned within a burr hole (not shown) of a skull (not shown) ofthe subject, and the upper flange portion 110 of the device 100 may beimplanted between the skull and the scalp of the subject. An externalcatheter 600 may be coupled to an external catheter connector (notshown) of the implantable cranial medical device 100 and positionedalong the skull of the subjected and tunneled to a position in thepatient remote from the implantable cranial medical device 100. Forexample, the external catheter 600 may be operably coupled to aninfusion device implanted subcutaneously in a location of a torso, suchas in the abdomen region, of the subject.

The brain catheter 300 may have any suitable length, such as about 6centimeters to about 7 centimeters, which should be sufficient toconnect to the implantable cranial medical device 100 and extend intothe lateral ventricle 400 of the brain 500 of the subject.

Use

The implantable cranial medical devices and associated devices describedherein may be used in any suitable mater. If the distal end portion ofthe brain catheter is positioned in a CSF-containing space of thesubject, the implantable cranial medical device may be permit infusionof therapeutic fluid and aspiration of CSF through separate lumens ofthe brain catheter and through separate fluid paths of the device.

For example, fluid may be aspirated from the CSF-containing space of thesubject through the first lumen of the brain catheter and through thefirst fluid path of the implantable cranial medical device. A lumen of aneedle may be placed in communication with the first fluid path of theimplantable cranial medical device. For example, the needle may beinserted into a port in communication with the first fluid path. Thefluid may be aspirated from the CSF-containing space of the subjectthrough lumen of the needle.

In some embodiments, the first fluid path of the implantable cranialmedical device and the first lumen of the brain catheter may be used toinfuse fluid, such as a fluid comprising a therapeutic agent, into theCSF-containing space of the subject. For example, a lumen of a needlemay be placed in communication with the first fluid path of theimplantable cranial medical device. For example, the needle may beinserted into a port in communication with the first fluid path. Thefluid may be infused through the lumen of the needle, through the firstfluid path of the implantable cranial medical device, and through thefirst lumen of the brain catheter to the CSF-containing space of thesubject.

A fluid may be infused to the CSF-containing space of the subject byinfusing the fluid through the second flow path of the implantablecranial medical device and through the second lumen of the braincatheter. The fluid may comprise a therapeutic agent. An infusion devicemay be coupled to the second fluid path of the implantable cranialmedical device, such as via an external catheter, and the fluid may beinfused from the infusion device to the CSF-containing space. Theinfusion device may be an implanted infusion device.

By providing separate lumens and fluid paths, infusion and aspiration(or infusion) may be conducted simultaneously. Accordingly, infusion ofa first therapeutic fluid does not need to be disrupted to aspirate asample of CSF or to introduce a second therapeutic fluid to the CSF.Such lack of disruption of infusion of the first therapeutic fluid mayprovide for improved therapy.

The devices, kits, and systems described herein may extend the space andtime a therapeutic agent is available to its brain target improvingpharmacokinetics and pharmacodynamics of the therapeutic agent in thebrain relative to prior approaches for direct infusion into the centralnervous system.

CSF aspirated via the first fluid path may be used for any suitablepurpose. For example, aspirated CSF may be used to determine theconcentration of a therapeutic agent, which may be introduced via atherapeutic fluid infused through the second fluid path to the CSF. Theflow rate or pattern of infused therapeutic may be adjusted based onconcentrations of therapeutic agent determined to be present in theaspirated CSF.

The aspirated CSF may be used to determine whether the subject may havean infection due to implantation or use of the implantable cranialmedical device and associated devices. If, for example, infectiousbacteria, fungi, or viruses are detected in the aspirated CSF,antibiotics, anti-fungal agents, or antiviral agents may be administeredto the CSF through, for example the first fluid flow path of the cranialmedical device and first lumen of the brain catheter. Concentration orpresence of infectious pathogens in subsequently aspirated CSF may beused to determine whether parameters of therapy should be adjusted orwhether the cranial medical device and associated devices should beexplanted.

The aspirated CSF may be used to detect or diagnose serious bacterial,fungal and viral infections, including meningitis, encephalitis andsyphilis. The aspirated CSF may be used to detect or diagnose bleedingaround the brain (subarachnoid hemorrhage). The aspirated CSF may beused to detect or diagnose certain cancers involving the brain or spinalcord. The aspirated CSF may be used to detect or diagnose certaininflammatory conditions of the nervous system, such as multiplesclerosis and Guillain-Barre syndrome.

For example, normal CSF white blood cell count is between 0 and 5, andnormal CSF red blood cell count is 0. An increase of white blood cellsmay indicate infection or inflammation, an increase in red blood cellcount may indicate bleeding into the cerebrospinal fluid.:

The aspirated CSF may be used to determine whether the presence orconcentration of a biological marker associated with the disease beingtreated changes in response to the infused therapeutic fluid. In fact,all diseases of the central nervous system have a CSF profile that isunique to the disease and to the progression of the disease. For ALS,markers may include a change in one or more molecules associated withinflammation. For Alzheimer’s disease markers may include beta amyloidand tau. For Huntington’s disease, a marker may include the hunitingtinprotein. For Parkinson’s disease, markers may include tau andleucine-rich repeat kinase 2 (LRRK-2).

The aspirated CSF may be used to determine the presence of biomarkersassociated with diagnosis and prognosis. Such biomarkers includemicroRNA such as miR-146a and miR-134 as biomarkers for epilepsydiagnosis and prognosis. The association of miR-146a and miR-134 andepilepsy is described in, for example, Leontariti, et al., “CirculatingmiR-146a and miR-134 in predicting epilepsy in patients with focalimpaired awareness seizures,” Epilepsia, May 2020 (e-published Apr. 21,2020); 61(5):959-970, which article is hereby incorporated herein byreference in its entirety to the extent that it does not conflict withthe disclosure presented herein.

As another example, a seizure event may cause a change in the CSFprofile of an individual. More specifically, immunoglobulin synthesis,elevated lactate, cell count, glucose and total protein concentrationsas well as blood-brain barrier dysfunction are frequently observable inthe CSF profile following epileptic seizures. Blood cell count may be amarker indicative of seizure disorder. For example, higher blood cellcounts may be indicative of more severe disorder and often longerhospital stays.

The infusion parameters or other parameters of therapy may be changedbased on the presence of concentration of the biological marker in theaspirated CSF.

The aspirated CSF may be used to determine whether the presence orconcentration of a biological marker indicative of toxicity of atherapeutic fluid infused into the CSF (e.g., via the second fluid pathand second lumen of the catheter). For example, the presence ofantibodies or other inflammatory response to the infused therapeuticagent may be indicative of potential toxicity of the infused therapeuticagent. The presence or increased concentrations of one or more of S100proteins, neuron specific enolase (NSE), tau, and beta-amyloid may beindicative of toxicity. If a biomarker indicative of toxicity isdetected in aspirated CSF, the rate of infusion of therapeutic fluid maybe reduced or infusion of the therapeutic fluid may be discontinued.

In some embodiments, intracranial pressure may be determined by placinga pressure monitor in fluid communication with the first fluid path ofthe implanted cranial medical device. For example, a needle operablycoupled to the pressure sensor may be placed in the port to determineintracranial pressure.

In some embodiments, aspirated CSF combined with therapeutic agents andthe infused back into the CSF-containing space.

In some embodiments, a dye or radioactive substances (ventriculograpy,cisternography) may be infused into cerebrospinal fluid to facilitatethe making of diagnostic images of the fluid’s flow within a subject’sbrain.

Any suitable therapeutic fluid may be infused through the first orsecond fluid path of the implantable cranial medical device and thefirst of second lumens of the brain catheter. The therapeutic fluid maycomprise any suitable therapeutic agent. Preferably, the therapeuticagent is an agent for treating a disease of the brain. Examples ofdiseases of the brain include any diseases with pathology or dysfunctionoccurring in any component of the brain (including the cerebralhemispheres, diencephalon, brain stem, and cerebellum) or the spinalcord. Examples include but are not limited to Parkinson’s disease,Alzheimer’s disease, dementia, Amyotrophic Lateral Sclerosis,Huntington’s disease, lysosomal storage diseases, post-traumatic stressdisorder, anxiety, depression, brain tumors, autism, autism spectrumdisorder, closed head injury, spinal cord injury, stroke, multiplesclerosis, schizophrenia, anxiety, and epilepsy. Preferably, theimplantable cranial medical device and associated devices are used totreat a disease of the brain that is resistant to treatment throughsystemic routes of administration, such as oral, intravenous,intramuscular, and intraperitoneal administration. The implantablecranial medical device and associated devices may also be used if apatient is at serious risk if direct central administration of atherapeutic fluid is not commenced.

The therapeutic fluid may be infused into the CSF or other brain regionat any suitable rate. Preferably, flow rate into the brain is limited to20 milliliters or less per day, such as 10 milliliters or less per day,or 5 milliliters per day or less. For example, the therapeutic fluid maybe infused at a metered rate of 4 milliliters per day or less, such as 3milliliters per day or less, 2 milliliters per day or less, or about 1milliliter per day.

Withdrawal of CSF from the brain should be limited to 3,500 millilitersper day or less, preferably 200 milliliters per day or less.

The therapeutic fluid may comprise any suitable therapeutic agent. Thetherapeutic agent selected may depend on the disease being treated. Thetherapeutic fluid, such as a solution, may contain any suitableconcentration of the therapeutic agent. The concentration of thetherapeutic agent will depend on the therapeutic agent employed. In someembodiments, the therapeutic fluid is a solution comprising atherapeutic agent at a concentration in a range of from about 10milligrams per milliliter to about 500 milligrams per milliliter, suchas from about 50 milligrams per milliliter to about 450 milligrams permilliliter.

For purposes of illustration, a list of suitable anti-epileptictherapeutic agent that may be included in a therapeutic fluid, such as asolution, includes carbamazepine; tiagabine, levetiracetam; lamotrigine;pregabalin; fenfluramine; gabapentin; phenytoin; topiramate;oxcarbazepine; valproate; valproic acid; zonisamide; perampanel;eslicarbazepine acetate; lacosamide; vigabatrin; rufinamide;fosphenytoin; ethosuximide; phenobarbital; diazepam; lorazepam;clonazepam; clobazam; ezogabine; felbamate; primidone; acetazolamide;brivaracetam; clorazepate; ethotoin; mephenytoin; methsuximide;trimethadione; bumetanide; adenosine; and an adenosine al receptoragonist. In some embodiment, the therapeutic agent is valproic acid or apharmacologically acceptable salt thereof. For purposes of the presentdisclosure, reference to a compound includes reference to salts,hydrates, solvates, and polymorphs thereof.

Examples of other therapeutic agents that may be delivered using animplantable cranial medical device for treating or diagnosing a CNSdisease include Edaravone (e.g., Radicava®) for Amyotrophic LateralSclerosis (ALS), Valbenazine (e.g., Ingrezza®) for Tardive dyskinesia,Deuterabenazine (e.g., Austedo®) for Huntington’s disease, Ocrelizumab(e.g., Ocrevus®) for Multiple sclerosis, Safinamide (e.g., Xadago®) forParkinson’s disease, Nusinersen (e.g., Spinraza®) for Spinal muscularatrophy (SMA), Daclizumab (e.g., Zinbryta®) for Multiple sclerosis,Pivavanserin (e.g., Nuplazid®) for Hallucinations and delusionsassociated with psychosis, Ariprprazole lauroxil (e.g., Aristada®) forSchizophrenia, Caripazine (e.g., Vraylar®) for Schizophrenia and bipolardisorder, Brexpiprazole (e.g., Rexulti®) for Schizophrenia,Peginterferon beta-la (e.g., Plegridy®) for Multiple sclerosis,Eslicarbazepine acetate (Aptiom®) for Epilepsy associated seizures,Flutemetamol F 18 (e.g., Vizamyl®) Radioactive diagnostic forAlzheimer’s disease, Vortioxetine (e.g., Brintellix®) for Majordepressive disorder, Dimethyl fumerate (e.g., Tecfidera®) for multiplesclerosis, and Gadoterate megumine (e.g., Dotarem®) for MRI-based brainimaging.

Examples of other therapeutic agents that may be delivered using animplantable cranial medical device as described herein include drugs andbiologics such as Coagulation Factors, Cytokines, Epigenetic proteinfamilies, Growth Factors, Hormones, Peptides, Signal Transductionmolecules, and mutations thereof; also including Amino Acids, Vaccinesand/or combinations thereof. Therapeutic compounds further includeantibodies, antisense, RNA interference made to the above biologics andtheir target receptors and mutations of thereof. Additional therapeuticcompounds include Gene Therapy, Primary and Embryonic Stem Cells. Alsoincluded in the therapeutic compounds are antibodies, antisense, RNAinterference to Protein Kinases, Esterases, Phosphatases, Ion channels,Proteases, structural proteins, membrane transport proteins, nuclearhormone receptors and/or combinations thereof.

Examples of Coagulation Factors include, but are not limited to:Fibrinogen, Prothrombin, Factor I, Factor V, Factor X, Factor VII,Factor VIII, Factor XI, Factor XIII, Protein C, Platelets,Thromboplastin, and Co-factor of VIIa.

Examples of Cytokines include, but are not limited to: Lymphokines,Interleukins, Chemokines, Monokines, Interferons, and Colony stimulatingfactors.

Examples of Epigenetic protein families include, but are not limited to:ATPase family AAA domain-containing protein 2 (ATAD2A), ATPasefamily-AAA domain containing 2B (ATAD2B), ATPase family AAA domaincontaining-2B (ATAD2B), bromodomain adjacent to zinc finger domain-1A(BAZ1A), bromodomain adjacent to zinc finger domain-1B (BAZ1B),bromodomain adjacent to zinc finger domain-2A (BAZ2A), bromodomainadjacent to zinc finger domain-2A (BAZ2A), bromodomain adjacent to zincfinger domain-2B (BAZ2B), bromodomain-containing protein 1 (BRD 1),Bromodomain containing protein 2—1st bromodomain (BRD2), Bromodomaincontaining protein 2—1st & 2nd bromodomains (BRD2),bromodomain-containing protein 2 isoform 1—bromodomain 2 (BRD2(2)),bromodomain-containing protein 3-bromodomain 1 (BRD3(1)),Bromodomain-containing protein 3—1st bromodomain (BRD3),Bromodomain-containing protein 3—1st & 2nd bromodomains (BRD3),bromodomain-containing protein 3-bromodomain 2 (BRD3(2)), Bromodomaincontaining protein 4—1st bromodomain (BRD4), bromodomain-containingprotein 4 isoform long-bromodomains 1 and 2 (BRD4(1-2)),bromodomain-containing protein 4 isoform long-bromodomain 2 (BRD4(2)),bromodomain-containing protein 4 isoform short(BRD4(full-length-short-iso.)), Bromodomain containing protein 7 (BRD7),bromodomain containing 8-bromodomain 1 (BRD8(1)), bromodomain containing8-bromodomain 2 (BRD8(2)), bromodomain-containing protein 9 isoform 1(BRD9), Bromodomain containing testis-specific— 1st bromodomain (BRDT),Bromodomain containing testis-specific—1st & 2nd bromodomains (BRDT),bromodomain testis-specific protein isoform b—bromodomain 2 (BRDT(2)),bromodomain and PHD finger containing—1 (BRPF1), bromodomain and PHDfinger containing-3 (BRPF3), bromodomain and PHD finger containing-3(BRPF3), Bromodomain and WD repeat-containing 3-2nd bromodomain(BRWD3(2)), Cat eye syndrome critical region protein 2 (CECR2), CREBbinding protein (CREBBP), E1A binding protein p300 (EP300), EP300(EP300), nucleosome-remodeling factor subunit BPTF isoform 1 (FALZ),Nucleosome-remodeling factor subunit BPT (FALZ), Euchromatichistone-lysine N-methyltransferase 2 (EHMT2), HistoneAcetyltransferase-KAT2A (GCN5L2), Euchromatic histone-lysineN-methyltransferase 1 (EHMT1), Histone-lysine N-methyltransferase MLL(MLL), Polybromo 1— 1st bromodomain (PB1(1)), Polybromo 1-2ndbromodomain (PB1(2)), polybromo 1-bromodomain 2 (PBRM1(2)), polybromo1-bromodomain 5 (PBRM1(5)), Histone acetyltransferase KAT2B (PCAF),PH-interacting protein—1st bromodomain (PHIP(1)), PH-interactingprotein-2nd bromodomain (PHIP(2)), Protein kinase C-binding protein 1(PRKCBP1), Protein arginine N-methyltransferase 3 (PRMT3), SWI/SNFrelated-matrix associated-actin dependent regulator ofchromatin-subfamily a—member 2 (SMARCA2), SWI/SNF related-matrixassociated-actin dependent regulator of chromatin-subfamily a— member 4(SMARCA4), Nuclear body protein-SP110 (SP110), Nuclear bodyprotein-SP140 (SP140), Transcription initiation factor TFIID subunit 1(TAF1(1-2)), TAF1 RNA polymerase II-TATA box binding protein(TBP)-associated factor-250 kDa-bromodomain 2 (TAF1(2)), Transcriptioninitiation factor TFIID subunit 1-like—1st bromodomain (TAF1L(1)),Transcription initiation factor TFIID subunit 1-like-2nd bromodomain(TAF1L(2)), tripartite motif containing 24 (TRIM24(Bromo.)), tripartitemotif containing 24 (TRIM24(PHD-Bromo.)), E3 ubiquitin-protein ligaseTRIM33 (TRIM33), tripartite motif containing 33 (TRIM33(PHD-Bromo.)), WDrepeat 9—1st bromodomain (WDR9(1)), and WD repeat 9—2nd bromodomain(WDR9(2)).

Examples of growth factors include, but are not limited to: nerve growthfactor (NGF), vascular endothelial growth factor (VEGF),platelet-derived growth factor (PDGF), C-fos-induced growth factor(FIGF), platelet-activating factor (PAF), transforming growth factorbeta (TGF-β), bone morphogenetic proteins (BMPs), Activin, inhibin,fibroblast growth factors (FGFs), granulocyte-colony stimulating factor(G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF),glial cell line-derived neurotrophic factor (GDNF), growthdifferentiation factor-9 (GDF9), epidermal growth factor (EGF),transforming growth factor-α (TGF-α), growth factor (KGF),migration-stimulating factor (MSF), hepatocyte growth factor-likeprotein (HGFLP), hepatocyte growth factor (HGF), hepatoma-derived growthfactor (HDGF), and Insulin-like growth factors.

Examples of Hormones include, but are not limited to: Amino acid derived(such as melatonin and thyroxine), Thyrotropin-releasing hormone,Vasopressin, Insulin, Growth Hormones, Glycoprotein Hormones,Luteinizing Hormone, Follicle-stimulating Hormone, Thyroid-stimulatinghormone, Eicosanoids, Arachidonic acid, Lipoxins, Prostaglandins,Steroid, Estrogens, Testosterone, Cortisol, and Progestogens.

Examples of Proteins and Peptides and Signal Transduction moleculesinclude, but are not limited to: Ataxia Telangiectasia Mutated, TumorProtein p53, Checkpoint kinase 2, breast cancer susceptibility protein,Double-strand break repair protein, DNA repair protein RAD50, Nibrin,p53-binding protein, Mediator of DNA damage checkpoint protein, H2Ahistone family member X, Microcephalin, C-terminal-binding protein 1,Structural maintenance of chromosomes protein 1A, Cell division cycle 25homolog A (CDC25A), forkhead box O3 (forkhead box O3), nuclear factor ofkappa light polypeptide gene enhancer in B-cells inhibitor, alpha(NFKBIA), nuclear factor (erythroid-derived 2)-like 2 (NFE2L2),Natriuretic peptide receptor A (NPR1), Tumor necrosis factor receptorsuperfamily, member 11a (TNFRSF11A), v-rel reticuloendotheliosis viraloncogene homolog A (avian) (RELA), Sterol regulatory element bindingtranscription factor 2 (SREBF2), CREB regulated transcriptioncoactivator 1 (CRTC1), CREB regulated transcription coactivator 2(CRTC2), X-box binding protein 1 (XBP1), Catenin beta 1(cadherin-associated protein or CTNNB1).

Another example is Dominant Negative Tumor Necrosis Factor (DN-TNF) suchas XPRO®1595 and the like.

Examples of G Protein-Coupled Receptors (GPCR) include, but are notlimited to: Adenosine receptor family, Adrenergic receptor family,Angiotensin II receptor, Apelin receptor, Vasopressin receptor family,Brain-specific angiogenesis inhibitor family, Bradykinin receptorfamily, Bombesin receptor family, Complement component 3a receptor 1,Complement component 5a receptor 1, Calcitonin receptor family,Calcitonin receptor-like family, Calcium-sensing receptor,Cholecystokinin A receptor (CCK1), Cholecystokinin B receptor (CCK2),Chemokine (C-C motif) receptor family, Sphingosine 1-phosphate receptorfamily, Succinic receptor, Cholinergic receptor family. Chemokine-likereceptor family, Cannabinoid receptor family, Corticotropin releasinghormone receptor family, prostaglandin D2 receptor, Chemokine C-X3-Creceptor family, Chemokine (C-X-C motif) receptor family, Burkittlymphoma receptor, Chemokine (C-X-C motif) receptor family, Cysteinylleukotriene receptor 2 (CYSLT2), chemokine receptor (FY), Dopaminereceptor family, G protein-coupled receptor 183 (GPR183),Lysophosphatidic acid receptor family, Endothelin receptor family,Coagulation factor II (thrombin) receptor family, Free fatty acidreceptor family, Formylpeptide receptor family, Follicle stimulatinghormone receptor (FSHR), gamma-aminobutyric acid (GABA) B receptor,Galanin receptor family, Glucagon receptor, Growth hormone releasinghormone receptor (GHRH), Ghrelin receptor (ghrelin), Growth hormonesecretagogue receptor 1b (GHSR1b), Gastric inhibitory polypeptidereceptor (GIP), Glucagon-like peptide receptor family,Gonadotropin-releasing hormone receptor (GnRH), pyroglutamylated RFamidepeptide receptor (QRFPR), G protein-coupled bile acid receptor 1 (GPBA),Hydroxycarboxylic acid receptor family, Lysophosphatidic acid receptor 4(LPA4) Lysophosphatidic acid receptor 5 (GPR92), G protein-coupledreceptor 79 pseudogene (GPR79), Hydroxycarboxylic acid receptor 1(HCA1), G-protein coupled receptor (C5L2, FFA4, FFA4, FFA4, GPER, GPR1,GPR101, GPR107, GPR119, GPR12, GPR123, GPR132, GPR135, GPR139, GPR141,GPR142, GPR143, GPR146, GPR148, GPR149, GPR15, GPR150, GPR151, GPR152,GPR157, GPR161, GPR162, GPR17, GPR171, GPR173, GPR176, GPR18, GPR182,GPR20, GPR22, GPR25, GPR26, GPR27, GPR3, GPR31, GPR32, GPR35, GPR37L1,GPR39, GPR4, GPR45, GPR50, GPR52, GPR55, GPR6, GPR61, GPR65, GPR75,GPR78, GPR83, GPR84, GPR85, GPR88, GPR97, TM7SF1), Metabotropicglutamate receptor family, Gastrin releasing peptide receptor (BB2),Orexin receptor family, Histamine receptor family, 5-hydroxytryptaminereceptor family, KISS1-derived peptide receptor (kisspeptin),Leucine-rich repeat-containing G protein-coupled receptor family,horiogonadotropin receptor (LH), Leukotriene B4 receptor (BLT1),Adenylate Cyclase Activating Polypeptide 1 Receptor 1 (mPAC1), Motilinreceptor, Melanocortin receptor family, Melanin concentrating hormonereceptor 1 (MCH1), Neuropeptide Y1 receptor (Y1), Neuropeptide Y2receptor (NPY2R), Opioid receptor family, Oxytocin recepter (OT), P2YPurinoceptor 12 (mP2Y12), P2Y Purinoceptor 6 (P2Y6), Pancreaticpolypeptide receptor family, Platelet-activating factor receptor family,Prostaglandin E receptor family, Prostanoid IP1 receptor (IP1),MAS-related GPR, member family, Rhodopsin (Rhodopsin), Relaxin familypeptide receptor family, Somatostatin receptor family, Tachykininreceptor family, Melatonin receptor family, Urotensin receptor family,Vasoactive intestinal peptide receptor 1 (mVPAC1), Neuromedin B Receptor(BB1), Neuromedin U receptor 1 (NMU1), Neuropeptides B/W receptorfamily, Neuropeptide FF receptor 1 (NPFF1), neuropeptide S receptor 1(NPS receptor), Neuropeptide Y receptor family, Neurotensin receptor 1(NTS1), Opsin 5 (OPN5), Opioid receptor-like receptor (NOP),Oxoeicosanoid (OXE) receptor 1 (OXE), Oxoglutarate (alpha-ketoglutarate)receptor 1 (OXGR1), Purinergic receptor family, Pyrimidinergic receptorfamily, Prolactin releasing hormone receptor (PRRP), Prokineticinreceptor family, Platelet activating receptor (PAF), Prostaglandin Freceptor family, Prostaglandin 12 (prostacyclin) receptor family,Parathyroid hormone receptor family, muscarinic acetylcholine receptors(such as rM4), Prostanoid DP2 receptor (rGPR44), Prokineticin receptorfamily, Relaxin family peptide receptor family, Secretin receptor(secretin), Frizzled class receptor (Smoothened), trace amine associatedreceptor family, Tachykinin family, Thromboxane A2 receptor (TP),Thyrotropin-releasing hormone receptor (TRH1), and Thyroid StimulatingHormone Receptor (TSH).

Examples of nuclear hormone receptors include, but are not limited to:Androgen receptor (AR), Estrogen related receptor alpha (ESRRA),Estrogen receptor 1 (ESR1), Nuclear receptor subfamily 1-group H-member4 (NR1H4), Nuclear receptor subfamily 3—group C— member 1(glucocorticoid receptor) (NR3C1), Nuclear receptor subfamily 1-groupH-member 3 (Liver X receptor α) (NR1H3), Nuclear receptor subfamily1-group H-member 2 (Liver X receptor β) (NR1H2), Nuclear receptorsubfamily 1-group H-member 2 (Liver X receptor β) (NR1H2), Nuclearreceptor subfamily 3—group C-member 2 (Mineralcorticoid receptor)(NR3C2), Peroxisome Proliferator Activated Receptor alpha (PPARA),Peroxisome Proliferator Activated Receptor gamma (PPARG), PeroxisomeProliferator Activated Receptor delta (PPARD), Progesterone receptor α(PGR), Progesterone receptor β (PGR), Retinoic acid receptor —alpha(RARA), Retinoic acid receptor —beta (RARB), Retinoid X receptor —alpha(RXRA), Retinoid X receptor —gamma (RXRG), Thyroid hormone receptor—alpha (THRA), Thyroid hormone receptor —beta (THRB), Retinoicacid-related orphan receptor, Liver X receptor, Farnesoid X receptor,Vitamin D receptor, Pregnane X receptor, Constitutive androstanereceptor, Hepatocyte nuclear factor 4, Oestrogen receptor,Oestrogen-related receptor, Glucocortioic receptor, and Nerve growthfactor-induced-B, Germ cell nuclear factor.

Examples of membrane transport proteins include, but are not limited to:ATP-binding cassette (ABC) superfamily, solute carrier (SLC)superfamily, multidrug resistance protein 1 (P-glycoprotein), organicanion transporter 1, and and proteins such as EAAT3, EAAC1, EAAT1,GLUT1, GLUT2, GLUT9, GLUT10, rBAT, AE1, NBC1, KNBC, CHED2, BTR1, NABC1,CDPD, SGLT1, SGLT2, NIS, CHT1, NET, DAT, GLYT2, CRTR, BOAT1, SIT1, XT3,y+LAT1, BAT1, NHERF1, NHE6, ASBT, DMT1, DCT1, NRAMP2, NKCC2, NCC, KCC3,NACT, MCT1, MCT8, MCT12, SLD, VGLUT3, THTR1, THTR2, PIT2, GLVR2, OCTN2,URAT1, NCKX1, NCKX5, CIC, PiC, ANTI, ORNT1, AGC1, ARALAR, Citrin, STLN2,aralar2, TPC, MUP1, MCPHA, CACT, GC1, PHC, DTD, CLD, DRA, PDS, Prestin,TAT1, FATP4, ENT3, ZnT2, ZnT10, AT1, NPT2A, NPT2B, HHRH, CST, CDG2F,UGAT, UGTL, UGALT, UGT1, UGT2, FUCT1, CDG2C, NST, PAT2, G6PT1, SPX4,ZIP4, LIV4, ZIP13, LZT-Hs9, FPN1, MTP1, IREG1, RHAG, AIM1, PCFT, FLVCR1,FLVCR2, RFT1, RFT2, RFT3, OATP1B1, OATPIB3, and OATP2A1.

Examples of structural proteins include, but are not limited to:tubulin, heat shock protein, Microtubule-stabilizing proteins,Oncoprotein 18, stathmin, kinesin-8 and kinesin-14 family, Kip3, andKif18A.

Examples of proteases include, but are not limited to, ADAM (adisintegrin and metalloprotease) family.

Examples of Protein kinases include, but are not limited to: AP2associated kinase, Homo sapiens ABL proto-oncogene 1-non-receptortyrosine-protein kinase family, c-abl oncogene 1 receptor tyrosinekinase family, v-abl Abelson murine leukemia viral oncogene homolog 2,activin A receptor family, chaperone -ABC1 activity of bc1 complexhomolog (S. pombe) (ADCK3), aarF domain containing kinase 4 (ADCK4),v-akt murine thymoma viral oncogene homolog family, anaplastic lymphomareceptor tyrosine kinase family, protein kinase A family, protein kinaseB family, ankyrin repeat and kinase domain containing 1 (ANKK1), NUAKfamily -SNF1-like kinase, mitogen-activated protein kinase kinase kinasefamily aurora kinase A (AURKA), aurora kinase B (AURKB), aurora kinase C(AURKC), AXL receptor tyrosine kinase (AXL), BMP2 inducible kinase(BIKE), B lymphoid tyrosine kinase (BLK), bone morphogenetic proteinreceptor family, BMX non-receptor tyrosine kinase (BMX), v-raf murinesarcoma viral oncogene homolog B1 (BRAF), protein tyrosine kinase 6(BRK), BR serine/threonine kinase family, Bruton agammaglobulinemiatyrosine kinase (BTK), calcium/calmodulin-dependent protein kinasefamily, cyclin-dependent kinase family, cyclin-dependent kinase-likefamily, CHK1 checkpoint homolog (S. pombe) (CHEK1), CHK2 checkpointhomolog (S. pombe) (CHEK2), Insulin receptor, isoform A (INSR), Insulinreceptor, isoform B (INSR), rho-interacting serine/threonine kinase(CIT), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog(KIT), CDC-Like Kinase family-Hepatocyte growth factor receptor (MET),Proto-oncogene tyrosine-protein kinase receptor, colony-stimulatingfactor family receptor, c-src tyrosine kinase (CSK), casein kinasefamily, megakaryocyte-associated tyrosine kinase (CTK), death-associatedprotein kinase family, doublecortin-like kinase family, discoidin domainreceptor tyrosine kinase, dystrophia myotonica-protein kinase (DMPK),dual-specificity tyrosine-(Y)-phosphorylation regulated kinase family,epidermal growth factor receptor family, eukaryotic translationinitiation factor 2-alpha kinase 1 (EIF2AK1), EPH receptor family,Ephrin type-A receptor family, Ephrin type-B receptor family, v-erb-b2erythroblastic leukemia viral oncogene homolog family, mitogen-activatedprotein kinase family, endoplasmic reticulum to nucleus signaling 1(ERN1), PTK2 protein tyrosine kinase 2 (FAK), fer (fps/fes related)tyrosine kinase (FER). feline sarcoma oncogene (FES), Fibroblast growthfactor receptor family, Gardner-Rasheed feline sarcoma viral (v-fgr)oncogene homolog (FGR), fms-related tyrosine kinase family, Fms-relatedtyrosine kinase family, fyn-related kinase (FRK), FYN oncogene relatedto SRC, cyclin G associated kinase (GAK), eukaryotic translationinitiation factor 2 alpha kinase, Growth hormone receptor. Gprotein-coupled receptor kinase 1 (GRK1), G protein-coupled receptorkinase family, glycogen synthase kinase family, germ cell associated 2(haspin) (HASPIN), Hemopoietic cell kinase (HCK), homeodomaininteracting protein kinase family, mitogen-activated protein kinasekinase kinase kinase family, hormonally up-regulated Neu-associatedkinase (HUNK), intestinal cell (MAK-like) kinase (ICK), Insulin-likegrowth factor 1 receptor (IGFIR), conserved helix-loop-helix ubiquitouskinase (IKK-alpha), inhibitor of kappa light polypeptide gene enhancerin B-cells —kinase beta family, insulin receptor (INSR), insulinreceptor-related receptor (INSRR), interleukin-1 receptor-associatedkinase family, IL2-inducible T-cell kinase (ITK), Janus kinase family,Kinase Insert Domain Receptor, v-kit Hardy-Zuckerman 4 feline sarcomaviral oncogene homolog, lymphocyte-specific protein tyrosine kinase(LCK), LIM domain kinase family, serine/threonine kinase familyleucine-rich repeat kinase family, v-yes-1 Yamaguchi sarcoma viralrelated oncogene homolog (LYN), male germ cell-associated kinase (MAK);MAP/microtubule affinity-regulating kinase family such as microtubuleassociated serine/threonine kinase family, maternal embryonic leucinezipper kinase, c-mer proto-oncogene tyrosine kinase (MERTK), metproto-oncogene (hepatocyte growth factor receptor), MAP kinaseinteracting serine/threonine kinase family, myosin light chain kinasefamily, mixed lineage kinase domain-like protein isoform, CDC42 bindingprotein kinase family, serine/threonine kinase family, macrophagestimulating 1 receptor (c-met-related tyrosine kinase) (MST1R),mechanistic target of rapamycin (serine/threonine kinase) (MTOR),muscle-skeletal-receptor tyrosine kinase (MUSK), myosin light chainkinase family, NIMA (never in mitosis gene a)-related kinase family,serine/threonine-protein kinase NIM1 (NIM1), nemo-like kinase (NLK),oxidative-stress responsive 1 (OSR1), p21 protein (Cdc42/Rac)-activatedkinase family, PAS domain containing serine/threonine kinase,Platelet-derived growth factor receptor family, 3-phosphoinositidedependent protein kinase-1 (PDPK1), Calcium-dependent protein kinase 1,phosphorylase kinase gamma family, Phosphatidylinositol 4,5-bisphosphate 3-kinase, phosphoinositide-3-kinase family,phosphatidylinositol 4-kinase family. phosphoinositide kinase, FYVEfinger containing, Pim-1 oncogene (PIM1), pim-2 oncogene (PIM2), pim-3oncogene (PIM3), phosphatidylinositol-4-phosphate 5-kinase family,phosphatidylinositol-5-phosphate 4-kinase family protein kinase,membrane associated tyrosine/threonine 1 (PKMYT1), protein kinase Nfamily, polo-like kinase family, protein kinase C family, protein kinaseD family, cGMP-dependent protein kinase family, eukaryotic translationinitiation factor 2-alpha kinase 2 (PRKR), X-linked protein kinase(PRKX), Prolactin receptor (PRLR), PRP4 pre-mRNA processing factor 4homolog B (yeast) (PRP4), PTK2B protein tyrosine kinase 2 beta (PTK2B),SIK family kinase 3 (QSK), v-raf-1 murine leukemia viral oncogenehomolog 1 (RAF1), Neurotrophic tyrosine kinase receptor type family,receptor (TNFRSF)-interacting serine-threonine kinase family, dualserine/threonine and tyrosine protein kinase (RIPK5), Rho-associated,coiled-coil containing protein kinase family, c-ros oncogene 1, receptortyrosine kinase (ROS1), ribosomal protein S6 kinase family, SH3-bindingdomain kinase 1 (SBK1), serum/glucocorticoid regulated kinase family,Putative uncharacterized serine/threonine-protein kinase (Sugen kinase110) (SgK110), salt-inducible kinase family, SNF related kinase (SNRK),src-related kinase, SFRS protein kinase family; Spleen tyrosine kinase(SYK) such as TAO kinase family; TANK-binding kinase 1 (TBK1) such astec protein tyrosine kinase (TEC), testis-specific kinase 1 (TESK1),transforming growth factor, beta receptor family, tyrosine kinase withimmunoglobulin-like and EGF-like domains 1 (TIE1), TEK tyrosine kinase,endothelial (TIE2), Angiopoietin-1 receptor (Tie2), tousled-like kinasefamily, TRAF2 and NCK interacting kinase (TN IK), non-receptor tyrosinekinase family, TNNI3 interacting kinase (TNNI3K), transient receptorpotential cation channel, testis-specific serine kinase family, TTKprotein kinase (TTK), TXK tyrosine kinase (TXK), Tyrosine kinase 2(TYK2), TYRO3 protein tyrosine kinase (TYRO3), unc-51-like kinasefamily, phosphatidylinositol 3-kinase, vaccinia related kinase 2 (VRK2),WEE1 homolog family, WNK lysine deficient protein kinase family, v-yes-1Yamaguchi sarcoma viral oncogene homolog 1 (YES), sterile alpha motifand leucine zipper containing kinase AZK (ZAK), and zeta-chain (TCR)associated protein kinase 70 kDa (ZAP70).

Cell therapy using cells that are derived primarily from: endoderm suchas Exocrine secretory epithelial cells and Hormone-secreting cells;ectoderm such as Keratinizing epithelial cells, Wet stratified barrierepithelial cells, Sensory transducer cells, Autonomic neuron cells,Sense organ and peripheral neuron supporting cells, Central nervoussystem neurons and glial cells, Lens cells; mesoderm such as Metabolismand storage cells, Barrier function cells (lung, gut, exocrine glandsand urogenital tract), Extracellular matrix cells, Contractile cells,Blood and immune system cells, Germ cells, Nurse cell, Interstitialcells and combinations thereof.

Examples of Exocrine secretory epithelial cells include but are notlimited to: Salivary gland mucous cell, Salivary gland number 1, VonEbner’s gland cell in tongue, Mammary gland cell, Lacrimal gland cell,Ceruminous gland cell in ear, Eccrine sweat gland dark cell, Eccrinesweat gland clear cell, Apocrine sweat gland cell, Gland of Moll cell ineyelid, Sebaceous gland cell, Bowman’s gland cell in nose, Brunner’sgland cell in duodenum, Seminal vesicle cell, Prostate gland cell,Bulbourethral gland cell, Bartholin’s gland cell, Gland of Littre cell,Uterus endometrium cell, Isolated goblet cell of respiratory anddigestive tracts, Stomach lining mucous cell, Gastric gland zymogeniccell, Gastric gland oxyntic cell, Pancreatic acinar cell, Paneth cell ofsmall intestine, Type II pneumocyte of lung, and Clara cell of lung;Hormone-secreting cells including, but not limited to: Anteriorpituitary cells, Intermediate pituitary cell, Magnocellularneurosecretory cells, Gut and respiratory tract cells, Thyroid glandcells, Parathyroid gland cells, Adrenal gland cells, Leydig cell oftestes secreting testosterone, Theca interna cell of ovarian folliclesecreting estrogen, Corpus luteum cell of ruptured ovarian folliclesecreting progesterone, Juxtaglomerular cell, Macula densa cell ofkidney, Peripolar cell of kidney, Mesangial cell of kidney, andPancreatic islets; Keratinizing epithelial cells including, but notlimited to: Epidermal keratinocyte, Epidermal basal cell, Keratinocyteof fingernails and toenails, Nail bed basal cell, Medullary hair shaftcell, Cortical hair shaft cell, Cuticular hair shaft cell, Cuticularhair root sheath cell, Hair root sheath cell of Huxley’s layer, Hairroot sheath cell of Henle’s layer, External hair root sheath cell, andHair matrix cell; Wet stratified barrier epithelial cells including, butnot limited to: Surface epithelial cell of stratified squamousepithelium and basal cell of epithelia of cornea, tongue, oral cavity,esophagus, anal canal, distal urethra and vagina, and Urinary epitheliumcell; Sensory transducer cells including, but not limited to: Auditoryinner hair cell of organ of Corti, Auditory outer hair cell of organ ofCorti, Basal cell of olfactory epithelium, Cold-sensitive primarysensory neurons, Heat-sensitive primary sensory neurons, Merkel cell ofepidermis, Olfactory receptor neuron, Pain-sensitive primary sensoryneurons, Photoreceptor cells of retina in eye, Proprioceptive primarysensory neurons, Touch-sensitive primary sensory neurons, Type I carotidbody cell, Type II carotid body cell, Type I hair cell of vestibularsystem of ear, Type II hair cell of vestibular system of ear, and Type Itaste bud cell; Autonomic neuron cells including, but not limited to:Cholinergic neural cell, Adrenergic neural cell, and Peptidergic neuralcell; Sense organ and peripheral neuron supporting cells including, butnot limited to: Inner pillar cell of organ of Corti, Outer pillar cellof organ of Corti, Inner phalangeal cell of organ of Corti, Outerphalangeal cell of organ of Corti, Border cell of organ of Corti, Hensencell of organ of Corti, Vestibular apparatus supporting cell, Taste budsupporting cell, Olfactory epithelium supporting cell, Schwann cell,Satellite glial cell, and Enteric glial cell; Central nervous systemneurons and glial cells including, but not limited to: Astrocyte, Neuroncells, Oligodendrocyte, and Spindle neuron; Lens cells including, butnot limited to: Anterior lens epithelial cell, and Crystallin-containinglens fiber cell; Metabolism and storage cells including, but not limitedto: Adipocytes, and Liver lipocyte; Barrier function cells including,but not limited to: Kidney parietal cell, Kidney glomerulus podocyte,Kidney proximal tubule brush border cell, Loop of Henle thin segmentcell, Kidney distal tubule cell, Kidney collecting duct cell, Principalcells, Intercalated cells, Type I pneumocyte, Pancreatic duct cell,Nonstriated duct cell, Principal cell, Intercalated cell, Duct cell,Intestinal brush border cell, Exocrine gland striated duct cell, Gallbladder epithelial cell, Ductulus efferens nonciliated cell, Epididymalprincipal cell, and Epididymal basal cell; Extracellular matrix cellsincluding, but not limited to: Ameloblast epithelial cell, Planumsemilunatum epithelial cell of vestibular system of ear, Organ of Cortiinterdental epithelial cell, Loose connective tissue fibroblasts,Corneal fibroblasts, Tendon fibroblasts, Bone marrow reticular tissuefibroblasts, Other nonepithelial fibroblasts, Pericyte, Nucleus pulposuscell of intervertebral disc, Cementoblast/cementocyte,Odontoblast/odontocyte, Hyaline cartilage chondrocyte, Fibrocartilagechondrocyte, Elastic cartilage chondrocyte, Osteoblast/osteocyte,Osteoprogenitor cell, Hyalocyte of vitreous body of eye, Stellate cellof perilymphatic space of ear, Hepatic stellate cell, and Pancreaticstelle cell; Contractile cells including, but not limited to: Skeletalmuscle cell, Satellite cell, Heart muscle cells, Smooth muscle cell,Myoepithelial cell of iris, and Myoepithelial cell of exocrine glands;Blood and immune system cells including, but not limited to:Erythrocyte, Megakaryocyte, Monocyte, Connective tissue macrophage,Epidermal Langerhans cell, Osteoclast, Dendritic cell, Microglial cell,Neutrophil granulocyte, Eosinophil granulocyte, Basophil granulocyte,Hybridoma cell, Mast cell, Helper T cell, Suppressor T cell, Cytotoxic Tcell, Natural Killer T cell, B cell, Natural killer cell, Reticulocyte,Stem cells, and committed progenitors for the blood and immune system;Germ cells including, but not limited to: Oogonium/Oocyte, Spermatid,Spermatocyte, Spermatogonium cell, and Spermatozoon; Nurse cellincluding, but not limited to: Ovarian follicle cell, and Sertoli cell,Thymus epithelial cell; Interstitial cells including, but not limitedto: Interstitial kidney cells and any combination of the foregoing.

Non-limiting examples of other known biologics include, but are notlimited to: Abbosynagis, Abegrin, Actemra, AFP-Cide, Antova, Arzerra,Aurexis, Avastin, Benlysta, Bexxar, Blontress, Bosatria, Campath,CEA-Cide, CEA-Scan, Cimzia, Cyramza, Ektomab, Erbitux, FibriScint,Gazyva, Herceptin, hPAM4-Cide, HumaSPECT, HuMax-CD4, HuMax-EGFr, Humira,HuZAF, Hybri-ceaker, Ilaris, Indimacis-125, Kadcyla, Lemtrada,LeukArrest, LeukoScan, Lucentis, Lymphomun, LymphoScan, LymphoStat-B,MabThera, Mycograb, Mylotarg, Myoscint, NeutroSpec, Numax, Nuvion,Omnitarg, Opdivo, Orthoclone OKT3, OvaRex, Panorex, Prolia, Prostascint,Raptiva, Remicade, Removab, Rencarex, ReoPro, Rexomun, Rituxan,RoActemra, Scintimun, Simponi, Simulect, Soliris, Stelara, Synagis,Tactress, Theracim, Theragyn, Theraloc, Tysabri, Vectibix, Verluma,Xolair, Yervoy, Zenapax, and Zevalin and combinations thereof.

Non-limiting examples of known Monoclonal antibodies include, but arenot limited to: 3F8, 8H9, Abagovomab, Abciximab, Abituzumab, Abrilumab,Actoxumab, Adalimumab, Adecatumumab, Aducanumab, Afasevikumab,Afelimomab, Afutuzumab, Alacizumab pegol, ALD518, ALD403, Alemtuzumab,Alirocumab, Altumomab pentetate, Amatuximab, AMG 334, Anatumomabmafenatox, Anetumab ravtansine, Anifrolumab, Anrukinzumab, Apolizumab,Arcitumomab, Ascrinvacumab, Aselizumab, Atezolizumab, Atinumab,Atlizumab, Atorolimumab, Avelumab, Bapineuzumab, Basiliximab,Bavituximab, Bectumomab, Begelomab, Belimumab, Benralizumab,Bertilimumab, Besilesomab, Bevacizumab, Bezlotoxumab, Biciromab,Bimagrumab, Bimekizumab, Bivatuzumab mertansine, Bleselumab,Blinatumomab, Blontuvetmab, Blosozumab, Bococizumab, Brazikumab,Brentuximab vedotin, Briakinumab, Brodalumab, Brolucizumab,Brontictuzumab, Burosumab, Cabiralizumab, Canakinumab, Cantuzumabmertansine, Cantuzumab ravtansine, Caplacizumab, Capromab pendetide,Carlumab, Carotuximab, Catumaxomab, cBR96-doxorubicin immunoconjugate,Cedelizumab, Cergutuzumab amunaleukin, Certolizumab pegol, Cetuximab,Citatuzumab bogatox, Cixutumumab, Clazakizumab, Clenoliximab,Clivatuzumab tetraxetan, Codrituzumab, Coltuximab ravtansine,Conatumumab, Concizumab, CR6261, Crenezumab, Crotedumab, Dacetuzumab,Daclizumab, Dalotuzumab, Dapirolizumab pegol, Daratumumab, Dectrekumab,Demcizumab, Denintuzumab mafodotin, Denosumab, Depatuxizumab mafodotin,Derlotuximab biotin, Detumomab, Dinutuximab, Diridavumab, Domagrozumab,Dorlimomab aritox, Drozitumab, Duligotumab, Dupilumab, Durvalumab,Dusigitumab, Ecromeximab, Eculizumab, Edobacomab, Edrecolomab,Efalizumab, Efungumab, Eldelumab, Elgemtumab, Elotuzumab, Elsilimomab,Emactuzumab, Emibetuzumab, Emicizumab, Enavatuzumab, Enfortumab vedotin,Enlimomab pegol, Enoblituzumab, Enokizumab, Enoticumab, Ensituximab,Epitumomab cituxetan, Epratuzumab, Erenumab, Erlizumab, Ertumaxomab,Etaracizumab, Etrolizumab, Evinacumab, Evolocumab, Exbivirumab,Fanolesomab, Faralimomab, Farletuzumab, Fasinumab, FBTA05, Felvizumab,Fezakinumab, Fibatuzumab, Ficlatuzumab, Figitumumab, Firivumab,Flanvotumab, Fletikumab, Fontolizumab, Foralumab, Foravirumab,Fresolimumab, Fulranumab, Futuximab, Galcanezumab, Galiximab, Ganitumab,Gantenerumab, Gavilimomab, Gemtuzumab ozogamicin, Gevokizumab,Girentuximab, Glembatumumab vedotin, Golimumab, Gomiliximab, Guselkumab,Ibalizumab, Ibritumomab tiuxetan, Icrucumab, Idarucizumab, Igovomab,IMA-638, IMAB362, Imalumab, Imciromab, Imgatuzumab, Inclacumab,Indatuximab ravtansine, Indusatumab vedotin, Inebilizumab, Infliximab,Inolimomab, Inotuzumab ozogamicin, Intetumumab, Ipilimumab, Iratumumab,Isatuximab, Itolizumab, Ixekizumab, Keliximab, Labetuzumab,Lambrolizumab, Lampalizumab, Lanadelumab, Landogrozumab, Laprituximabemtansine, LBR-101/PF0442g7429, Lebrikizumab, Lemalesomab, Lendalizumab,Lenzilumab, Lerdelimumab, Lexatumumab, Libivirumab, Lifastuzumabvedotin, Ligelizumab, Lilotomab satetraxetan, Lintuzumab, Lirilumab,Lodelcizumab, Lokivetmab, Lorvotuzumab mertansine, Lucatumumab,Lulizumab pegol, Lumiliximab, Lumretuzumab, LY2951742, Mapatumumab,Margetuximab, Maslimomab, Matuzumab, Mavrilimumab, Mepolizumab,Metelimumab, Milatuzumab, Minretumomab, Mirvetuximab soravtansine,Mitumomab, Mogamulizumab, Monalizumab, Morolimumab, Motavizumab,Moxetumomab pasudotox, Muromonab-CD3, Nacolomab tafenatox, Nam ilumab,Naptumomab estafenatox, Naratuximab emtansine, Narnatumab, Natalizumab,Navicixizumab, Navivumab, Nebacumab, Necitumumab, Nemolizumab,Nerelimomab, Nesvacumab, Nimotuzumab, Nivolumab, Nofetumomab merpentan,Obiltoxaximab, Obinutuzumab, Ocaratuzumab, Ocrelizumab, Odulimomab,Ofatumumab, Olaratumab, Olokizumab, Omalizumab, Onartuzumab,Ontuxizumab, Opicinumab, Oportuzumab monatox, Oregovomab, Orticumab,Otelixizumab, Otlertuzumab, Oxelumab, Ozanezumab, Ozoralizumab,Pagibaximab, Palivizumab, Pamrevlumab, Panitumumab, Pankomab,Panobacumab, Parsatuzumab, Pascolizumab, Pasotuxizumab, Pateclizumab,Patritumab, Pembrolizumab, Pemtumomab, Perakizumab, Pertuzumab,Pexelizumab, Pidilizumab, Pinatuzumab vedotin, Pintumomab, Placulumab,Plozalizumab, Pogalizumab, Polatuzumab vedotin, Ponezumab, Prezalizumab,Priliximab, Pritoxaximab, Pritumumab, PRO 140, Quilizumab, Racotumomab,Radretumab, Rafivirumab, Ralpancizumab, Ramucirumab, Ranibizumab,Raxibacumab, Refanezumab, Regavirumab, Reslizumab, Rilotumumab,Rinucumab, Risankizumab, Rituximab, Rivabazumab pegol, Robatumumab,Roledumab, Romosozumab, Rontalizumab, Rovalpituzumab tesirine,Rovelizumab, Ruplizumab, Sacituzumab govitecan, Samalizumab,Sapelizumab, Sarilumab, Satumomab pendetide, Secukinumab, Seribantumab,Setoxaximab, Sevirumab, SGN-CD19A, SGN-CD33A, Sibrotuzumab, Sifalimumab,Siltuximab, Simtuzumab, Siplizumab, Sirukumab, Sofituzumab vedotin,Solanezumab, Solitomab, Sonepcizumab, Sontuzumab, Stamulumab, Sulesomab,Suvizumab, Tabalumab, Tacatuzumab tetraxetan, Tadocizumab, Talizumab,Tamtuvetmab, Tanezumab, Taplitumomab paptox, Tarextumab, Tefibazumab,Telimomab aritox, Tenatumomab, Teneliximab, Teplizumab, Teprotumumab,Tesidolumab, Tetulomab, Tezepelumab, TGN1412, Ticilimumab, Tigatuzumab,Tildrakizumab, Timolumab, Tisotumab vedotin, TNX-650, Tocilizumab,Toralizumab, Tosatoxumab, Tositumomab, Tovetumab, Tralokinumab,Trastuzumab, Trastuzumab emtansine, TRBS07, Tregalizumab, Tremelimumab,Trevogrumab, Tucotuzumab celmoleukin, Tuvirumab, Ublituximab,Ulocuplumab, Urelumab, Urtoxazumab, Ustekinumab, Utomilumab,Vadastuximab talirine, Vandortuzumab vedotin, Vantictumab, Vanucizumab,Vapaliximab, Varlilumab, Vatelizumab, Vedolizumab, Veltuzumab,Vepalimomab, Vesencumab, Visilizumab, Vobarilizumab, Volociximab,Vorsetuzumab mafodotin, Votumumab, Xentuzumab, Zalutumumab, Zanolimumab,Zatuximab, Ziralimumab, and Zolimomab aritox and combinations thereof.

Examples of vaccines developed for viral diseases include, but are notlimited to: Hepatitis A vaccine, Hepatitis B vaccine, Hepatitis Evaccine, HPV vaccine, Influenza vaccine, Japanese encephalitis vaccine,MMR vaccine, MMRV vaccine, Polio vaccine, Rabies vaccine, Rotavirusvaccine, Varicella vaccine, Shingles vaccine, Smallpox vaccine, YellowFever vaccine, Adenovirus vaccine, Coxsackie B virus vaccine,Cytomegalovirus vaccine, Dengue vaccine for humans, Eastern Equineencephalitis virus vaccine for humans, Ebola vaccine, Enterovirus 71vaccine, Epstein-Barr vaccine, Hepatitis C vaccine, HIV vaccine, HTLV-1T-lymphotropic leukemia vaccine for humans, Marburg virus diseasevaccine, Norovirus vaccine, Respiratory syncytial virus vaccine forhumans, Severe acute respiratory syndrome (SARS) vaccine, West Nilevirus vaccine for humans; Examples of bacterial diseases include but arenot limited to: Anthrax vaccines, DPT vaccine, Q fever vaccine, Hibvaccine, Tuberculosis (BCG) vaccine, Meningococcal vaccine, Typhoidvaccine, Pneumococcal conjugate vaccine, Pneumococcal polysaccharidevaccine, Cholera vaccine, Caries vaccine, Ehrlichiosis vaccine, Leprosyvaccine, Lyme disease vaccine, Staphylococcus aureus vaccine,Streptococcus pyogenes vaccine, Syphilis vaccine, Tularemia vaccine, andYersinia pestis vaccine; Examples of parasitic diseases include, but arenot limited to: Malaria vaccine, Schistosomiasis vaccine, Chagas diseasevaccine, Hookworm vaccine, Onchocerciasis river blindness vaccine forhumans, Trypanosomiasis vaccine, and Visceral leishmaniasis vaccine;Examples of non-infectious diseases include, but are not limited to:Alzheimer’s disease amyloid protein vaccine, Breast cancer vaccine,Ovarian cancer vaccine, Prostate cancer vaccine, and Talimogenelaherparepvec (T-VEC); also vaccines including, but not limited to thefollowing trade names: ACAM2000, ActHIB, Adacel, Afluria, AFLURIAQUADRIVALENT, Agriflu, BCG Vaccine, BEXSERO, Biothrax, Boostrix,Cervarix, Comvax, DAPTACEL, DECAVAC, Engerix-B, FLUAD, Fluarix, FluarixQuadrivalent, Flublok, Flucelvax, Flucelvax Quadrivalent, FluLaval,FluMist, FluMist Quadrivalent, Fluvirin, Fluzone Quadrivalent, Fluzone,Fluzone High-Dose and Fluzone Intradermal, Gardasil, Gardasil 9, Havrix,Hiberix, Imovax, Infanrix, IPOL, Ixiaro, JE-Vax, KINRIX, Menactra,MenHibrix, Menomune-A/C/Y/W-135, Menveo, M-M-R II, M-M-Vax, Pediarix,PedvaxHIB, Pentacel, Pneumovax 23, Poliovax, Prevnar, Prevnar 13,ProQuad, Quadracel, Quadrivalent, RabAvert, Recombivax HB, ROTARIX,RotaTeq, TENIVAC, TICE BCG, Tripedia, TRUMENBA, Twinrix, TYPHIM Vi,VAQTA, Varivax, Vaxchora, Vivotif, YF-Vax, Zostavax, and combinationsthereof.

Examples of injectable drugs include, but are not limited to: Ablavar(Gadofosveset Trisodium Injection), Abarelix Depot, Abobotulinumtoxin AInjection (Dysport), ABT-263, ABT-869, ABX-EFG, Accretropin (SomatropinInjection), Acetadote (Acetylcysteine Injection), AcetazolamideInjection (Acetazolamide Injection), Acetylcysteine Injection(Acetadote), Actemra (Tocilizumab Injection), Acthrel (CorticorelinOvine Triflutate for Injection), Actummune, Activase, Acyclovir forInjection (Zovirax Injection), Adacel, Adalimumab, Adenoscan (AdenosineInjection), Adenosine Injection (Adenoscan), Adrenaclick, AdreView(Iobenguane 1123 Injection for Intravenous Use), Afluria, Ak-Fluor(Fluorescein Injection), Aldurazyme (Laronidase), Alglucerase Injection(Ceredase), Alkeran Injection (Melphalan Hcl Injection), AllopurinolSodium for Injection (Aloprim), Aloprim (Allopurinol Sodium forInjection), Alprostadil, Alsuma (Sumatriptan Injection), ALTU-238, AminoAcid Injections, Aminosyn, Apidra, Apremilast, Alprostadil Dual ChamberSystem for Injection (Caverject Impulse), AMG 009, AMG 076, AMG 102, AMG108, AMG 114, AMG 162, AMG 220, AMG 221, AMG 222, AMG 223, AMG 317, AMG379, AMG 386, AMG 403, AMG 477, AMG 479, AMG 517, AMG 531, AMG 557, AMG623, AMG 655, AMG 706, AMG 714, AMG 745, AMG 785, AMG 811, AMG 827, AMG837, AMG 853, AMG 951, Amiodarone HCl Injection (Amiodarone HClInjection), Amobarbital Sodium Injection (Amytal Sodium), Amytal Sodium(Amobarbital Sodium Injection), Anakinra, Anti-Abeta, Anti-Beta7,Anti-Beta20, Anti-CD4, Anti-CD20, Anti-CD40, Anti-IFNalpha, Anti-IL13,Anti-OX40L, Anti-oxLDS, Anti-NGF, Anti-NRP1, Arixtra, Amphadase(Hyaluronidase Inj), Ammonul (Sodium Phenylacetate and Sodium BenzoateInjection), Anaprox, Anzemet Injection (Dolasetron Mesylate Injection),Apidra (Insulin Glulisine [rDNA origin] Inj), Apomab, Aranesp(darbepoetin alfa), Argatroban (Argatroban Injection), ArginineHydrochloride Injection (R-Gene 10, Aristocort, Aristospan, ArsenicTrioxide Injection (Trisenox), Articane HCl and Epinephrine Injection(Septocaine), Arzerra (Ofatumumab Injection), Asclera (PolidocanolInjection), Ataluren, Ataluren-DMD, Atenolol Inj (Tenormin I.V.Injection), Atracurium Besylate Injection (Atracurium BesylateInjection), Avastin, Azactam Injection (Aztreonam Injection),Azithromycin (Zithromax Injection), Aztreonam Injection (AzactamInjection), Baclofen Injection (Lioresal Intrathecal), BacteriostaticWater (Bacteriostatic Water for Injection), Baclofen Injection (LioresalIntrathecal), Bal in Oil Ampules (Dimercarprol Injection), BayHepB,BayTet, Benadryl, Bendamustine Hydrochloride Injection (Treanda),Benztropine Mesylate Injection (Cogentin), Betamethasone InjectableSuspension (Celestone Soluspan), Bexxar, Bicillin C-R 900/300(Penicillin G Benzathine and Penicillin G Procaine Injection), Blenoxane(Bleomycin Sulfate Injection), Bleomycin Sulfate Injection (Blenoxane),Boniva Injection (Ibandronate Sodium Injection), Botox Cosmetic(OnabotulinumtoxinA for Injection), BR3-FC, Bravelle (UrofollitropinInjection), Bretylium (Bretylium Tosylate Injection), Brevital Sodium(Methohexital Sodium for Injection), Brethine, Briobacept, BTT-1023,Bupivacaine HCl, Byetta, Ca-DTPA (Pentetate Calcium Trisodium Inj),Cabazitaxel Injection (Jevtana), Caffeine Alkaloid (Caffeine and SodiumBenzoate Injection), Calcijex Injection (Calcitrol), Calcitrol (CalcijexInjection), Calcium Chloride (Calcium Chloride Injection 10%), CalciumDisodium Versenate (Edetate Calcium Disodium Injection), Campath(Altemtuzumab), Camptosar Injection (Irinotecan Hydrochloride),Canakinumab Injection (Ilaris), Capastat Sulfate (Capreomycin forInjection), Capreomycin for Injection (Capastat Sulfate), Cardiolite(Prep kit for Technetium Tc99 Sestamibi for Injection), Carticel,Cathflo, Cefazolin and Dextrose for Injection (Cefazolin Injection),Cefepime Hydrochloride, Cefotaxime, Ceftriaxone, Cerezyme, CarnitorInjection, Caverject, Celestone Soluspan, Celsior, Cerebyx (FosphenytoinSodium Injection), Ceredase (Alglucerase Injection), Ceretec (TechnetiumTc99m Exametazime Injection), Certolizumab, CF-101, ChloramphenicolSodium Succinate (Chloramphenicol Sodium Succinate Injection),Chloramphenicol Sodium Succinate Injection (Chloramphenicol SodiumSuccinate), Cholestagel (Colesevelam HCL), Choriogonadotropin AlfaInjection (Ovidrel), Cimzia, Cisplatin (Cisplatin Injection), Clolar(Clofarabine Injection), Clomiphine Citrate, Clonidine Injection(Duraclon), Cogentin (Benztropine Mesylate Injection), ColistimethateInjection (Coly-Mycin M), Coly-Mycin M (Colistimethate Injection),Compath, Conivaptan Hcl Injection (Vaprisol), Conjugated Estrogens forInjection (Premarin Injection), Copaxone, Corticorelin Ovine Triflutatefor Injection (Acthrel), Corvert (Ibutilide Fumarate Injection), Cubicin(Daptomycin Injection), CF-101, Cyanokit (Hydroxocobalamin forInjection), Cytarabine Liposome Injection (DepoCyt), Cyanocobalamin,Cytovene (ganciclovir), D.H.E. 45, Dacetuzumab, Dacogen (DecitabineInjection), Dalteparin, Dantrium IV (Dantrolene Sodium for Injection),Dantrolene Sodium for Injection (Dantrium IV), Daptomycin Injection(Cubicin), Darbepoietin Alfa, DDAVP Injection (Desmopressin AcetateInjection), Decavax, Decitabine Injection (Dacogen), Dehydrated Alcohol(Dehydrated Alcohol Injection), Denosumab Injection (Prolia),Delatestryl, Delestrogen, Delteparin Sodium, Depacon (Valproate SodiumInjection), Depo Medrol (Methylprednisolone Acetate InjectableSuspension), DepoCyt (Cytarabine Liposome Injection), DepoDur (MorphineSulfate XR Liposome Injection), Desmopressin Acetate Injection (DDAVPInjection), Depo-Estradiol, Depo-Provera 104 mg/ml, Depo-Provera 150mg/ml, Depo-Testosterone, Dexrazoxane for Injection, IntravenousInfusion Only (Totect), Dextrose/Electrolytes, Dextrose and SodiumChloride Inj (Dextrose 5% in 0.9% Sodium Chloride), Dextrose, DiazepamInjection (Diazepam Injection), Digoxin Injection (Lanoxin Injection),Dilaudid-HP (Hydromorphone Hydrochloride Injection), DimercarprolInjection (Bal in Oil Ampules), Diphenhydramine Injection (BenadrylInjection), Dipyridamole Injection (Dipyridamole Injection), DMOAD,Docetaxel for Injection (Taxotere), Dolasetron Mesylate Injection(Anzemet Injection), Doribax (Doripenem for Injection), Doripenem forInjection (Doribax), Doxercalciferol Injection (Hectorol Injection),Doxil (Doxorubicin Hcl Liposome Injection), Doxorubicin Hcl LiposomeInjection (Doxil), Duraclon (Clonidine Injection), Duramorph (MorphineInjection), Dysport (Abobotulinumtoxin A Injection), EcallantideInjection (Kalbitor), EC-Naprosyn (naproxen), Edetate Calcium DisodiumInjection (Calcium Disodium Versenate), Edex (Alprostadil forInjection), Engerix, Edrophonium Injection (Enlon), Eliglustat Tartate,Eloxatin (Oxaliplatin Injection), Emend Injection (FosaprepitantDimeglumine Injection), Enalaprilat Injection (Enalaprilat Injection),Enlon (Edrophonium Injection), Enoxaparin Sodium Injection (Lovenox),Eovist (Gadoxetate Disodium Injection), Enbrel (etanercept), Enoxaparin,Epicel, Epinepherine, Epipen, Epipen Jr., Epratuzumab, Erbitux,Ertapenem Injection (Invanz), Erythropoieten, Essential Amino AcidInjection (Nephramine), Estradiol Cypionate, Estradiol Valerate,Etanercept, Exenatide Injection (Byetta), Evlotra, Fabrazyme (Adalsidasebeta), Famotidine Injection, FDG (Fludeoxyglucose F 18 Injection),Feraheme (Ferumoxytol Injection), Feridex I.V. (Ferumoxides InjectableSolution), Fertinex, Ferumoxides Injectable Solution (Feridex I.V.),Ferumoxytol Injection (Feraheme), Flagyl Injection (MetronidazoleInjection), Fluarix, Fludara (Fludarabine Phosphate), Fludeoxyglucose F18 Injection (FDG), Fluorescein Injection (Ak-Fluor), Follistim AQCartridge (Follitropin Beta Injection), Follitropin Alfa Injection(Gonal-f RFF), Follitropin Beta Injection (Follistim AQ Cartridge),Folotyn (Pralatrexate Solution for Intravenous Injection), Fondaparinux,Forteo (Teriparatide (rDNA origin) Injection), Fostamatinib,Fosaprepitant Dimeglumine Injection (Emend Injection), Foscarnet SodiumInjection (Foscavir), Foscavir (Foscarnet Sodium Injection),Fosphenytoin Sodium Injection (Cerebyx), Fospropofol Disodium Injection(Lusedra), Fragmin, Fuzeon (enfuvirtide), GA101, Gadobenate DimeglumineInjection (Multihance), Gadofosveset Trisodium Injection (Ablavar),Gadoteridol Injection Solution (ProHance), Gadoversetamide Injection(OptiMARK), Gadoxetate Disodium Injection (Eovist), Ganirelix (GanirelixAcetate Injection), Gardasil, GC1008, GDFD, Gemtuzumab Ozogamicin forInjection (Mylotarg), Genotropin, Gentamicin Injection, GENZ-112638,Golimumab Injection (Simponi Injection), Gonal-f RFF (Follitropin AlfaInjection), Granisetron Hydrochloride (Kytril Injection), GentamicinSulfate, Glatiramer Acetate, Glucagen, Glucagon, HAE1, Haldol(Haloperidol Injection), Havrix, Hectorol Injection (DoxercalciferolInjection), Hedgehog Pathway Inhibitor, Heparin, Herceptin, hG-CSF,Humalog, Human Growth Hormone, Humatrope, HuMax, Humegon, Humira,Humulin, Ibandronate Sodium Injection (Boniva Injection), IbuprofenLysine Injection (NeoProfen), Ibutilide Fumarate Injection (Corvert),Idamycin PFS (Idarubicin Hydrochloride Injection), IdarubicinHydrochloride Injection (Idamycin PFS), Ilaris (Canakinumab Injection),Imipenem and Cilastatin for Injection (Primaxin I.V.), Imitrex,Incobotulinumtoxin A for Injection (Xeomin), Increlex (Mecasermin [rDNAorigin] Injection), Indocin IV (Indomethacin Inj), Indomethacin Inj(Indocin IV), Infanrix, Innohep, Insulin, Insulin Aspart [rDNA origin]Inj (NovoLog), Insulin Glargine [rDNA origin] Injection (Lantus),Insulin Glulisine [rDNA origin] Inj (Apidra), Interferon alfa-2b,Recombinant for Injection (Intron A), Intron A (Interferon alfa-2b,Recombinant for Injection), Invanz (Ertapenem Injection), InvegaSustenna (Paliperidone Palmitate Extended-Release InjectableSuspension), Invirase (saquinavir mesylate), lobenguane 1123 Injectionfor Intravenous Use (AdreView), Iopromide Injection (Ultravist),Ioversol Injection (Optiray Injection), Iplex (Mecasermin Rinfabate[rDNA origin] Injection), Iprivask, Irinotecan Hydrochloride (CamptosarInjection), Iron Sucrose Injection (Venofer), Istodax (Romidepsin forInjection), Itraconazole Injection (Sporanox Injection), Jevtana(Cabazitaxel Injection), Jonexa, Kalbitor (Ecallantide Injection), KCLin D5NS (Potassium Chloride in 5% Dextrose and Sodium ChlorideInjection), KCL in D5W, KCL in NS, Kenalog 10 Injection (TriamcinoloneAcetonide Injectable Suspension), Kepivance (Palifermin), KeppraInjection (Levetiracetam), Keratinocyte, KFG, Kinase Inhibitor, Kineret(Anakinra), Kinlytic (Urokinase Injection), Kinrix, Klonopin(clonazepam), Kytril Injection (Granisetron Hydrochloride), lacosamideTablet and Injection (Vimpat), Lactated Ringer’s, Lanoxin Injection(Digoxin Injection), Lansoprazole for Injection (Prevacid I.V.), Lantus,Leucovorin Calcium (Leucovorin Calcium Injection), Lente (L), Leptin,Levemir, Leukine Sargramostim, Leuprolide Acetate, Levothyroxine,Levetiracetam (Keppra Injection), Lovenox, Levocarnitine Injection(Carnitor Injection), Lexiscan (Regadenoson Injection), LioresalIntrathecal (Baclofen Injection), Liraglutide [rDNA] Injection(Victoza), Lovenox (Enoxaparin Sodium Injection), Lucentis (RanibizumabInjection), Lumizyme, Lupron (Leuprolide Acetate Injection), Lusedra(Fospropofol Disodium Injection), Maci, Magnesium Sulfate (MagnesiumSulfate Injection), Mannitol Injection (Mannitol IV), Marcaine(Bupivacaine Hydrochloride and Epinephrine Injection), Maxipime(Cefepime Hydrochloride for Injection), MDP Multidose Kit of TechnetiumInjection (Technetium Tc99m Medronate Injection), Mecasermin [rDNAorigin] Injection (Increlex), Mecasermin Rinfabate [rDNA origin]Injection (Iplex), Melphalan Hcl Injection (Alkeran Injection),Methotrexate, Menactra, Menopur (Menotropins Injection), Menotropins forInjection (Repronex), Methohexital Sodium for Injection (BrevitalSodium), Methyldopate Hydrochloride Injection, Solution (MethyldopateHcl), Methylene Blue (Methylene Blue Injection), MethylprednisoloneAcetate Injectable Suspension (Depo Medrol), MetMab, MetoclopramideInjection (Reglan Injection), Metrodin (Urofollitropin for Injection),Metronidazole Injection (Flagyl Injection), Miacalcin, Midazolam(Midazolam Injection), Mimpara (Cinacalet), Minocin Injection(Minocycline Inj), Minocycline Inj (Minocin Injection), Mipomersen,Mitoxantrone for Injection Concentrate (Novantrone), Morphine Injection(Duramorph), Morphine Sulfate XR Liposome Injection (DepoDur), MorrhuateSodium (Morrhuate Sodium Injection), Motesanib, Mozobil (PlerixaforInjection), Multihance (Gadobenate Dimeglumine Injection), MultipleElectrolytes and Dextrose Injection, Multiple Electrolytes Injection,Mylotarg (Gemtuzumab Ozogamicin for Injection), Myozyme (Alglucosidasealfa), Nafcillin Injection (Nafcillin Sodium), Nafcillin Sodium(Nafcillin Injection), Naltrexone XR Inj (Vivitrol), Naprosyn(naproxen), NeoProfen (Ibuprofen Lysine Injection), Nandrol Decanoate,Neostigmine Methylsulfate (Neostigmine Methylsulfate Injection),NEO-GAA, NeoTect (Technetium Tc 99 m Depreotide Injection), Nephramine(Essential Amino Acid Injection), Neulasta (pegfilgrastim), Neupogen(Filgrastim), Novolin, Novolog, NeoRecormon, Neutrexin (TrimetrexateGlucuronate Inj), NPH (N), Nexterone (Amiodarone HCl Injection),Norditropin (Somatropin Injection), Normal Saline (Sodium ChlorideInjection), Novantrone (Mitoxantrone for Injection Concentrate), Novolin70/30 Innolet (70% NPH, Human Insulin Isophane Suspension and 30%Regular, Human Insulin Injection), NovoLog (Insulin Aspart [rDNA origin]Inj), Nplate (romiplostim), Nutropin (Somatropin (rDNA origin) for Inj),Nutropin AQ, Nutropin Depot (Somatropin (rDNA origin) for Inj),Octreotide Acetate Injection (Sandostatin LAR), Ocrelizumab, OfatumumabInjection (Arzerra), Olanzapine Extended Release Injectable Suspension(Zyprexa Relprevv), Omnitarg, Omnitrope (Somatropin [rDNA origin]Injection), Ondansetron Hydrochloride Injection (Zofran Injection),OptiMARK (Gadoversetamide Injection), Optiray Injection (IoversolInjection), Orencia, Osmitrol Injection in A viva (Mannitol Injection inAviva Plastic Vessel 250), Osmitrol Injection in Viaflex (MannitolInjection in Viaflex Plastic Vessel 250), Osteoprotegrin, Ovidrel(Choriogonadotropin Alfa Injection), Oxacillin (Oxacillin forInjection), Oxaliplatin Injection (Eloxatin), Oxytocin Injection(Pitocin), Paliperidone Palmitate Extended-Release Injectable Suspension(Invega Sustenna), Pamidronate Disodium Injection (Pam idronate DisodiumInjection), Panitumumab Injection for Intravenous Use (Vectibix),Papaverine Hydrochloride Injection (Papaverine Injection), PapaverineInjection (Papaverine Hydrochloride Injection), Parathyroid Hormone,Paricalcitol Injection Fliptop Vial (Zemplar Injection), PARP Inhibitor,Pediarix, PEGlntron, Peginterferon, Pegfilgrastim, Penicillin GBenzathine and Penicillin G Procaine, Pentetate Calcium Trisodium Inj(Ca-DTPA), Pentetate Zinc Trisodium Injection (Zn-DTPA), PepcidInjection (Famotidine Injection), Pergonal, Pertuzumab, PhentolamineMesylate (Phentolamine Mesylate for Injection), Physostigmine Salicylate(Physostigmine Salicylate (injection)), Physostigmine Salicylate(injection) (Physostigmine Salicylate), Piperacillin and TazobactamInjection (Zosyn), Pitocin (Oxytocin Injection), Plasma-Lyte 148(Multiple Electrolytes Inj), Plasma-Lyte 56 and Dextrose (MultipleElectrolytes and Dextrose Injection in Viaflex, Plastic Vessel 250),PlasmaLyte, Plerixafor Injection (Mozobil), Polidocanol Injection(Asclera), Potassium Chloride, Pralatrexate Solution for IntravenousInjection (Folotyn), Pramlintide Acetate Injection (Symlin), PremarinInjection (Conjugated Estrogens for Injection), Prep kit for TechnetiumTc99 Sestamibi for Injection (Cardiolite), Prevacid I.V. (Lansoprazolefor Injection), Primaxin I.V. (Imipenem and Cilastatin for Injection),Prochymal, Procrit, Progesterone, ProHance (Gadoteridol InjectionSolution), Prolia (Denosumab Injection), Promethazine HCl Injection(Promethazine Hydrochloride Injection), Propranolol HydrochlorideInjection (Propranolol Hydrochloride Injection), Quinidine GluconateInjection (Quinidine Injection), Quinidine Injection (QuinidineGluconate Injection), R-Gene 10 (Arginine Hydrochloride Injection),Ranibizumab Injection (Lucentis), Ranitidine Hydrochloride Injection(Zantac Injection), Raptiva, Reclast (Zoledronic Acid Injection),Recombivarix HB, Regadenoson Injection (Lexiscan), Reglan Injection(Metoclopramide Injection), Remicade, Renagel, Renvela (SevelamerCarbonate), Repronex (Menotropins for Injection), Retrovir IV(Zidovudine Injection), rhApo2L/TRAIL, Ringer’s and 5% DextroseInjection (Ringers in Dextrose), Ringer’s Injection (Ringers Injection),Rituxan, Rituximab, Rocephin (ceftriaxone), Rocuronium Bromide Injection(Zemuron), Roferon-A (interferon alfa-2a), Romazicon (flumazenil),Romidepsin for Injection (Istodax), Saizen (Somatropin Injection),Sandostatin LAR (Octreotide Acetate Injection), Sclerostin Ab, Sensipar(cinacalcet), Sensorcaine (Bupivacaine HCl Injections), Septocaine(Articane HCl and Epinephrine Injection), Serostim LQ (Somatropin (rDNAorigin) Injection), Simponi Injection (Golimumab Injection), SodiumAcetate (Sodium Acetate Injection), Sodium Bicarbonate (SodiumBicarbonate 5% Injection), Sodium Lactate (Sodium Lactate Injection inAVIVA), Sodium Phenylacetate and Sodium Benzoate Injection (Ammonul),Somatropin (rDNA origin) for Inj (Nutropin), Sporanox Injection(Itraconazole Injection), Stelara Injection (Ustekinumab), Stemgen,Sufenta (Sufentanil Citrate Injection), Sufentanil Citrate Injection(Sufenta), Sumavel, Sumatriptan Injection (Alsuma), Symlin, Symlin Pen,Systemic Hedgehog Antagonist, Synvisc-One (Hylan G-F 20 SingleIntra-articular Injection), Tarceva, Taxotere (Docetaxel for Injection),Technetium Tc 99 m, Telavancin for Injection (Vibativ), TemsirolimusInjection (Torisel), Tenormin I.V. Injection (Atenolol Inj),Teriparatide (rDNA origin) Injection (Forteo), Testosterone Cypionate,Testosterone Enanthate, Testosterone Propionate, Tev-Tropin (Somatropin,rDNA Origin, for Injection), tgAAC94, Thallous Chloride, Theophylline,Thiotepa (Thiotepa Injection), Thymoglobulin (Anti-Thymocyte Globulin(Rabbit), Thyrogen (Thyrotropin Alfa for Injection), TicarcillinDisodium and Clavulanate Potassium Galaxy (Timentin Injection), TiganInjection (Trimethobenzamide Hydrochloride Injectable), TimentinInjection (Ticarcillin Disodium and Clavulanate Potassium Galaxy),TNKase, Tobramycin Injection (Tobramycin Injection), TocilizumabInjection (Actemra), Torisel (Temsirolimus Injection), Totect(Dexrazoxane for Injection, Intravenous Infusion Only), Trastuzumab-DM1,Travasol (Amino Acids (Injection)), Treanda (Bendamustine HydrochlorideInjection), Trelstar (Triptorelin Pamoate for Injectable Suspension),Triamcinolone Acetonide, Triamcinolone Diacetate, TriamcinoloneHexacetonide Injectable Suspension (Aristospan Injection 20 mg),Triesence (Triamcinolone Acetonide Injectable Suspension),Trimethobenzamide Hydrochloride Injectable (Tigan Injection),Trimetrexate Glucuronate Inj (Neutrexin), Triptorelin Pamoate forInjectable Suspension (Trelstar), Twinject, Trivaris (TriamcinoloneAcetonide Injectable Suspension), Trisenox (Arsenic Trioxide Injection),Twinrix, Typhoid Vi, Ultravist (Iopromide Injection), Urofollitropin forInjection (Metrodin), Urokinase Injection (Kinlytic), Ustekinumab(Stelara Injection), Ultralente (U), Valium (diazepam), Valproate SodiumInjection (Depacon), Valtropin (Somatropin Injection), VancomycinHydrochloride (Vancomycin Hydrochloride Injection), VancomycinHydrochloride Injection (Vancomycin Hydrochloride), Vaprisol (ConivaptanHcl Injection), VAQTA, Vasovist (Gadofosveset Trisodium Injection forIntravenous Use), Vectibix (Panitumumab Injection for Intravenous Use),Venofer (Iron Sucrose Injection), Verteporfin Inj (Visudyne), Vibativ(Telavancin for Injection), Victoza (Liraglutide [rDNA] Injection),Vimpat (lacosamide Tablet and Injection), Vinblastine Sulfate(Vinblastine Sulfate Injection), Vincasar PFS (Vincristine SulfateInjection), Victoza, Vincristine Sulfate (Vincristine SulfateInjection), Visudyne (Verteporfin Inj), Vitamin B-12, Vivitrol(Naltrexone XR Inj), Voluven (Hydroxyethyl Starch in Sodium ChlorideInjection), Xeloda, Xenical (orlistat), Xeomin (Incobotulinumtoxin A forInjection), Xolair, Zantac Injection (Ranitidine HydrochlorideInjection), Zemplar Injection (Paricalcitol Injection Fliptop Vial),Zemuron (Rocuronium Bromide Injection), Zenapax (daclizumab), Zevalin,Zidovudine Injection (Retrovir IV), Zithromax Injection (Azithromycin),Zn-DTPA (Pentetate Zinc Trisodium Injection), Zofran Injection(Ondansetron Hydrochloride Injection), Zingo, Zoledronic Acid for Inj(Zometa), Zoledronic Acid Injection (Reclast), Zometa (Zoledronic Acidfor Inj), Zosyn (Piperacillin and Tazobactam Injection), ZyprexaRelprevv (Olanzapine Extended Release Injectable Suspension) andcombinations thereof.

Preferably, the first fluid flow path is free of a microbial filter. Bylacking a microbial filter the first fluid flow path may be used towithdraw CSF that may have cells or other large molecules without suchcells or large molecules being filtered. The first fluid flow path mayalso be used to introduce therapeutic fluids that comprise cells orother large molecules.

The second fluid flow path may comprise a microbial filter. Themicrobial filter may be positioned at any suitable location of thesecond fluid flow path.

Referring now to FIG. 15 , an implantable cranial device 100 includes afirst fluid flow path 192 extending from a first opening 116 in the topsurface 112 of the device 100 to a first opening 126 at the bottom ofthe device 100. The implantable cranial device 100 includes a secondfluid flow path 194 extending from a second opening 118 in an upperflange portion of the device 100 to a second opening 128 at the bottomof the device 100. The second upper flange portion opening 118 in thedepicted embodiment is defined by an external catheter connector 140.The first 126 and second 128 openings of the bottom of the device areformed by a brain catheter connector 130. The filter 499 is depicted asbeing in the second pathway 194 in proximity to the external catheterconnector 140. However, the filter 499 may be positioned at any suitablelocation in the second pathway 194.

System

The implantable cranial medical devices described herein and associateddevices, such as brain catheters, external catheters, and the like maybe used with any suitable external device or external devices. Theexternal devices may be infusion devices. The infusion device may beimplantable or non-implantable. The non-implantable infusion device maybe an ambulatory device or a stationary device. The infusion device maybe manually powered, electromechanically powered, chemically powered, orotherwise powered. In some examples, the infusion device may comprise apiston pump, a peristaltic pump, an osmotic pump, a plunger, or thelike. A distal portion of the CSF shunt or drainage catheter may beplaced in any suitable location of the patient, such as the peritonealcavity.

In some embodiments, more than one external device is connected to theimplantable cranial medical device in serial. For example, the devicesmay be “daisy-chained”. In some examples, a passive infusion device isfluidly positioned between the implantable cranial medical device and anactive infusion device, such a powered infusion device.

The passive device may be a modified Ommaya or Rickman reservoir. Thereservoirs may be modified such that they do not need to be coupled to acatheter implanted in the brain. Rather the reservoirs may be operablycoupled to the implantable cranial medical device, such as through thesecond fluid path, to deliver therapeutic fluid to the brain via thesecond lumen of the brain catheter. The reservoirs may be implantedunder the scalp. The reservoirs may contain ports for introducingneedles percutaneously to deliver therapeutic fluids. The reservoirs maycomprise appropriate valves to ensure one-way direction of flow from thereservoir to the implantable cranial medical device.

The use of such reservoirs may be beneficial if multiple manualinfusions of therapeutic agent are anticipated. Rather than repeatedlypercutaneously accessing the port of the implantable cranial medicaldevice to both aspirate CSF and infuse therapeutic fluid, the reservoirmay be used introduce the therapeutic fluid, thereby reducing the numberof times the skin in punctured over the port of the implantable cranialmedical device.

The passive infusion device or port may be fully implantable, partiallyimplantable or positioned external to a subject.

The port may be placed at a location to allow convenient access forintroduction of therapeutic fluid into the CSF-containing space of thesubject. For example, the second port may be located in proximity to thesubject’s ear (“auricular”) or in proximity to the subject’s clavicle(“clavicular”). The port may be configured to be implantedsubcutaneously on the skull in proximity to an ear or in implantedsubcutaneously in proximity to a clavicle.

The port may be used to introduce a fluid to a CSF-containing space viathe implantable cranial medical device. The fluid may be a therapeuticfluid. The port may be used to deliver the therapeutic fluid until thetherapy is determined to be effective. For example, the port may be usedto determine an appropriate therapeutic agent for use in the therapeuticfluid, an appropriate dose range, or the like. Once the therapy isdetermined effective, an infusion device may be operatively coupled tothe implantable cranial medical device to deliver the therapeutic fluidto the brain, e.g., to a CSF-containing space. The port may be replacedwith the infusion device. Alternatively, the port and the infusiondevice may both be operatively coupled with the implantable cranialmedical device.

Some therapies involve periodic, rather than continuous, infusion oftherapeutic fluid. For such therapies, the port may be used tochronically deliver periodic infusions of the therapeutic fluid to aCSF-containing space via the implantable cranial medical device.

Some therapies involve infusion of more than one therapeutic fluid. Forsuch therapies, an infusion device operatively coupled to theimplantable cranial medical device may be used to deliver a firsttherapeutic fluid to a CSF-containing space via the implantable cranialmedical device, and the port may be used deliver a second a secondtherapeutic fluid to the CSF-containing space via the implantablecranial medical device. The port may be used to deliver auxiliarytherapeutic fluids, to treat symptoms that may arise during infusion ofthe first therapeutic fluid, or the like.

Referring now to FIGS. 16 and 17 , schematic drawings of systems 1000are shown. The systems include an implantable cranial medical device 100and associated brain catheter 200. The system 1000 also includes anexternal catheter 600 operably coupled to a first 400 or second 500external device. In FIG. 16 , the implantable cranial medical device 100is connected to the first device 400 via the external catheter 600. InFIG. 17 , the implantable cranial medical device 100 is connected to thesecond device 500 via the external catheter 600, and the second device500 is connected to the first device 400 via an additional catheter 700.The first device 400 may be an implantable infusion device, such as apowered implantable infusion device. The second device 500 may be areservoir having a port accessible through the scalp of a subject, suchas a modified Ommaya or Rickman reservoir.

Reference is now made to FIGS. 18-21 , which illustrate some componentsof embodiments of systems described herein. FIG. 18 shows an implantablecranial medical device 100 implanted in a subject’s head and a port 500in proximity to the subject’s clavicle. The port 500 may be implanted ormay be external to the subject. The implantable cranial medical device100 and port 500 may be implanted in, or positioned in proximity to, anyother suitable location of the subject. A catheter 600 operativelycouples the implantable cranial medical device 100 to the port 500.

In FIG. 19 , the port 500 is disconnected from the catheter 600, and aninfusion device catheter 700 that is operatively coupled to an infusiondevice 400 is coupled to catheter 600. The infusion device catheter 700may be coupled to catheter 600 in any suitable manner. For example, asplice connector (not shown) having components similar to thosedescribed above regarding catheter connectors may be employed to couplethe infusion device catheter 700 to catheter 600. Preferably, theinfusion device 400 is implanted in the subject.

FIG. 20 illustrates an embodiment where an infusion device 400 isoperatively coupled to the port 500 via an infusion device catheter 700.The infusion device catheter 700 may be coupled to an additional inlet(not shown), such as via a catheter connector (not shown), of the port500. Preferably, the port 500 and the infusion device 400 are implanted.

FIG. 21 illustrates an embodiment in which an infusion device 400 isoperatively coupled to catheter 600 via an infusion device catheter 700while the port 500 is also coupled to catheter 600. Catheter 600 may bebifurcated at its proximal end portion to permit both the port 500 andthe infusion device 400 to be simultaneously operatively coupled to thecatheter 600. Alternatively, a Y-adapter or T-adapter (not shown) havingcomponents such as those described above regarding catheter connectorsmay be employed to operatively couple both the port 500 and the infusiondevice 400, via the infusion device catheter 700, to catheter 600.

FIG. 22 illustrates an embodiment of a port 500 configured to couple toan infusion device 400 and the implantable cranial medical device. Theport 500 includes a housing 510 that defines at least a portion of theouter surface of the second port. The housing 510 may define an openingthat serves as the third inlet 520. A self-sealing septum (not shown)may be disposed across the opening defining the third inlet 520. Theself-sealing septum may be as described above regarding a self-sealingseptum of the implantable cranial medical device. The third inlet 520may comprise a ferrule (not shown) and compression wedge (not shown) asdescribed above regarding the catheter connector of the implantablecranial medical device.

The port 500 may comprise a catheter connector 522 that defines anoutlet 524. The port 500 comprises a fluid pathway 526 that extends froman inlet 520 to the outlet 524. The catheter connector 522 maypositioned at any suitable location of the second port 500. In FIG. 22 ,the catheter connector 522 is positioned at a side surface of the port500. The catheter connector 522 is configured to operatively couple to acatheter to place a lumen of the catheter in fluid communication withthe fluid pathway 526. The catheter may also be coupled to the externalcatheter connector of the implantable cranial medical device. Thecatheter connector 522 of the port 500 may comprise components of acatheter connector as described above regarding the implantable cranialmedical device.

The port 500 may comprise an infusion device catheter connector 532. Theinfusion device catheter connector 532 defines an inlet 530. A fluidpathway 536 extends from the inlet 530 to the outlet 524. The infusiondevice catheter connector 532 is configured to operatively couple to aninfusion device catheter to place a lumen of the infusion devicecatheter in fluid communication with the fluid pathway 536. The infusiondevice catheter connector 522 of the port 500 may comprise components ofa catheter connector as described above regarding the implantablecranial medical device.

Device and System for Delivering to Fluid to or Withdrawing fromIntrathecal Space

The devices, systems, kits and methods described above are primarilydescribed in the context of their use for delivering therapeutic fluidsdirectly to the brain or withdrawing CSF from a region of the brain. Itwill be understood that the implantable cranial medical devices,catheters, systems, kits, and methods described herein may be used todeliver therapeutic agents to, or withdraw CSF from, the intrathecalspace.

The devices, systems and devices, systems, kits and methods may bemodified, as appropriate to deliver fluid to the intrathecal space. Forexample, the implantable cranial medical device may be modified forimplanting in fascia rather than under the scalp of a subject. Thedevice may be implanted in any suitable location of the patient, such asin the torso of the subject, near the back of the neck of the subject,or the like.

The shape of the device may be modified to accommodate the site ofimplantation. While the device may not maintain the shape, size anddimensions of the implantable cranial medical device described above,the functionality of the device may remain largely unchanged. That is,the device may comprise a first and second fluid flow paths andconnector for connecting one or more catheters (referred hereinafter asa “spinal catheter”), preferably a multi-lumen spinal catheter, that maybe placed in communication with the intrathecal space. The device maycomprise a port into which needles may be inserted to delivertherapeutic fluid to, or withdraw CSF from, the intrathecal space viathe first fluid flow path and first lumen of a spinal catheter. Thedevice may comprise external catheter connector for connecting to anexternal catheter to place a lumen of the external catheter incommunication with the second fluid flow path. The external catheter maybe used to connect to an external device or for draining CSF.

The length of a spinal catheter may be greater than the length of abrain catheter described above. The spinal catheter may be positioned inany suitable location of the intrathecal space. Preferably, the distaltip of the spinal catheter is positioned at cervical vertebral level orhigher. In some embodiments, the distal tip of the spinal catheter isadvanced through the intrathecal space into the cisterna magna.

The spinal catheter may have a length sufficient to be inserted into theintrathecal space and to be advanced to a higher vertebral level or thecisterna magna. The spinal catheter may be configured to enter theintrathecal space at any suitable vertebral level. For example, thespinal catheter may be configured to be introduced into the intrathecalspace at a lumbar vertebral level.

The spinal catheter may have an outer diameter greater than the outerdiameter of a brain catheter described above.

The spinal catheter may have multiple openings in fluid communicationwith an aspiration fluid flow path of the device accessible via theport. The multiple openings may be positioned any suitable distanceapart, such as about three inches to about seven inches, to allow forsampling of CSF at different locations along the spine, as differentbiomarkers or concentrations may be present at different CSF locations.The spinal catheter may have any suitable number of openings, such asthree, four, five, or more.

In some embodiments, the port has multiple aspiration fluid flow pathswith each aspiration path separately coupled with a lumen of a catheteror catheters. If the catheter is a multi-lumen catheter the distal endportion of the lumens may be separated by about three inches to aboutseven inches along the length of the catheter so that CSF may be sampledalong the length of the spinal canal. The multi-lumen spinal cathetermay have any suitable number of aspiration lumens, such as three, four,five or more.

In some embodiments, the device may have multiple spinal catheterconnectors with each spinal catheter connector configured to connect toa separate spinal catheter. In some embodiments, the first fluid path(the path in communication with the port) is in communication with morethan one catheter port. Spinal catheters having different lengths may becoupled to the spinal catheter connectors, so that the catheters may bepositioned within the intrathecal space at different vertebral levelsfor aspirating CSF along the length of the spinal canal.

The materials described above for the implantable cranial medicaldevice, brain catheter, and other system and kit components may be thesame for the device and spinal catheter for delivering therapeutic fluidto, or withdrawing fluid from, the intrathecal space.

The methods discussed above regarding the use of the implantable cranialmedical device, systems and kits may be employed using a device, system,or kit adapted for delivering therapeutic fluid to, or withdrawing fluidfrom, the intrathecal space.

Summary of Some Selected Aspects

Various aspects of implantable cranial medical devices, systems and kitsincluding implantable cranial medical devices, methods for implantingimplantable cranial medical devices and associated devices, and methodsfor using implantable cranial medical devices and associated devices arediscloses herein. A summary of some of the aspect is provided below.

In a first aspect, an implantable cranial medical device comprises afirst fluid path, a second fluid path, an upper flange portion, and alower portion. The upper flange portion is configured to rest on a skullof subject about a burr hole. The lower portion is configured to beplaced within the burr hole. The first fluid flow path extends from afirst opening in the upper flange portion to a first opening in thelower portion. The second fluid flow path from a second opening in theupper flange portion to a second opening in the lower portion.

In a second aspect, an implantable cranial medical device comprises afirst fluid path, a second fluid path, and upper flange portion, and alower portion. The upper flange portion has width in a range from 15millimeters to 30 millimeters. The lower portion has a width in a rangefrom 10 millimeters to 20 millimeters, wherein the upper flange portionhas a greater width than the lower portion. The first fluid path extendsfrom a first opening in the upper flange portion to a first opening inthe lower portion. The second fluid path extends from a second openingin the upper flange portion to a second opening in the lower portion

A third aspect is an implantable cranial medical device of the first orsecond aspect, wherein the lower portion has a height in a range from 3millimeters to 7 millimeters.

A fourth aspect is an implantable cranial medical device of any of thefirst three aspects, wherein the upper flange portion a height in arange from 3 millimeters to 8 millimeters.

A fifth aspect is an implantable cranial device of any one of the firstfour aspects, wherein the device comprises a housing, and wherein thehousing defines an outer surface of the upper flange portion and thelower portion.

A sixth aspect is an implantable cranial medical device of the fifthaspect, comprising a reservoir disposed in the housing, whereinreservoir is in communication with the first fluid path.

A seventh aspect is an implantable cranial medical device of the sixthaspect, wherein the reservoir has a volume in a range from 2 millilitersto 7 milliliters

An eighth seventh aspect is an implantable cranial medical device of anyof the first seven aspects, comprising a port defining an opening incommunication with the first fluid path.

A ninth aspect is an implantable cranial medical device of the eighthaspect, wherein the first opening of the upper flange portion definesthe opening of the port.

A tenth aspect is an implantable cranial medical device of the ninthaspect, wherein the upper flange portion comprises a top surface andwherein first opening of the upper flange portion is defined by the topsurface.

An eleventh aspect is as implantable cranial medical device of any oneof aspects 8-10, comprising a septum, wherein the septum seals theopening of the port.

A twelfth aspect is an implantable cranial medical device of any one ofaspects 1 to 11, comprising an external catheter connector incommunication with the second fluid path.

A thirteenth aspect is an implantable cranial medical device of thetwelfth aspect, wherein the external catheter connector comprises afitting configured to be inserted into a lumen of the external catheter.

A fourteenth aspect is an implantable cranial medical device of aspects12 or 13, wherein the external catheter connector has a longitudinalaxis that extends substantially parallel to a bottom of the upper flangeportion.

A fifteenth aspect is an implantable cranial medical device of any oneof aspects 1 to 14, wherein the upper flange portion of the housingcomprises a generally flat annular bottom extending laterally relativeto the lower portion.

A sixteenth aspect is an implantable cranial medical device of any oneof aspects 1 to 15, comprising a brain catheter connector extending fromthe lower portion, the catheter connector comprising a first lumen influid communication with the first fluid path and a second lumen influid communication with the second fluid path.

A seventeenth aspect is a system comprising the implantable cranialmedical device of aspect 16 and a brain catheter operably couplable tothe brain catheter connector, wherein the brain catheter comprises firstand second lumens, wherein the first lumen of the brain catheter isplaced in fluid communication with the first lumen of the brain catheterconnector when the brain catheter is coupled to the brain catheterconnector, and wherein the second lumen of the brain catheter is placedin fluid communication with the second lumen of the brain catheterconnector when the brain catheter is coupled to the brain catheterconnector

An eighteenth aspect is a system comprising the implantable cranialmedical device of any one of aspects 1 to 16 or the system of aspect 17and an implantable infusion device operably coupled to the second fluidpath.

A nineteenth aspect is a method comprising (i) implanting a braincatheter having a distal end and a proximal end and having first andsecond lumens extending from the proximal end to the distal end, whereinthe brain catheter is implanted such that the distal end is positionedin a CSF-containing space of a subject and the proximal end is inproximity to a burr hole in a skull of the subject, (ii) implanting theimplantable cranial medical device of any one of aspects 1 to 16 in asubject such that the lower portion of the housing is disposed in theburr hole and the upper flange portion is between a skull and a scalp ofthe subject; and (iii) coupling the brain catheter to the implantablecranial medical device such that the first lumen of the brain catheteris in communication with the first fluid path and the second lumen ofthe brain catheter is in communication with the second fluid path.

A twentieth aspect is a method of the nineteenth aspect, comprisingaspirating fluid from the CSF-containing space of the subject throughthe first lumen of the brain catheter and through the first fluid pathof the implantable cranial medical device.

A twenty-first aspect is a method of the twentieth aspect, comprisingplacing a lumen of a needle in communication with the first fluid pathof the implantable cranial medical device and aspirating the fluid fromthe CSF-containing space of the subject through the lumen of the needle.

A twenty-second aspect is a method of any one of aspects 19 to 21,comprising infusing a fluid to the CSF-containing space of the subjectby infusing the fluid through the second flow path of the implantablecranial medical device and through the second lumen of the braincatheter.

A twenty-third aspect is a method of the twenty-second aspect,comprising coupling an infusion device to the second fluid path of theimplantable cranial medical device and infusing the fluid from theinfusion device to the second fluid path.

A twenty-fourth aspect is a method of the twenty-third aspect, whereinthe infusion device is an implanted infusion device.

A twenty-fifth aspect is a method of any one of aspects 19 to 24,wherein the CSF-containing space is a cerebral ventricle.

All scientific and technical terms used herein have meanings commonlyused in the art unless otherwise specified. The definitions providedherein are to facilitate understanding of certain terms used frequentlyherein and are not meant to limit the scope of the present disclosure.

As used herein, singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. As used in thisspecification and the appended claims, the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise. The term “and/or” means one or all of the listedelements or a combination of any two or more of the listed elements.

The words “preferred” and “preferably” refer to embodiments of thedisclosure that may afford certain benefits, under certaincircumstances. However, other embodiments may also be preferred, underthe same or other circumstances. Furthermore, the recitation of one ormore preferred embodiments does not imply that other embodiments are notuseful and is not intended to exclude other embodiments from the scopeof the inventive technology.

Any direction referred to herein, such as “top,” “bottom,” “side,”“upper,” “lower,” and other directions or orientations are describedherein for clarity and brevity but are not intended to be limiting of anactual device or system. Devices and systems described herein may beused in a number of directions and orientations.

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatany particular order be inferred. Any recited single or multiple featureor aspect in any one claim can be combined or permuted with any otherrecited feature or aspect in any other claim or claims.

The headings used herein are for organizational purposes only and arenot meant to be used to limit the scope of the description. As usedthroughout this application, the word “may” is used in a permissivesense (i.e., meaning having the potential to), rather than the mandatorysense (i.e., meaning must).

The words “include,” “including,” and “includes” indicate open-endedrelationships and therefore mean including, but not limited to.Similarly, the words “have,” “having,” and “has” also indicatedopen-ended relationships, and thus mean having, but not limited to.Similarly, the terms “comprise” and “comprising” indicate open-endedrelationships, and thus mean comprising, but not limited to. The terms“consisting essentially of′ and “consisting of” are subsumed within theterm “comprising.” For example, a catheter comprising tubing may be acatheter consisting of tubing. The term “consisting essentially of”means a recited list of one or more items belonging to an article, kit,system, or method and other non-listed items that do not materiallyaffect the properties of the article, kit, system, or method.

The terms “first,” “second,” “third,” and so forth as used herein areused as labels for nouns that they precede, and do not imply any type ofordering (e.g., spatial, temporal, logical, etc.) unless such anordering is otherwise explicitly indicated. For example, a “second”feature does not require that a “first” feature be implemented prior tothe “second” feature, unless otherwise specified.

Various components may be described as “configured to” perform a task ortasks. In such contexts, “configured to” is a broad recitation generallymeaning “having structure that” performs the task or tasks duringoperation. As such, the component can be configured to perform the taskeven when the component is not currently performing that task (e.g., acatheter connector may be configured to place a lumen of a catheter influid communication with a fluid path, even when the catheter is notconnected to the catheter connector).

Various components may be described as performing a task or tasks, forconvenience in the description. Such descriptions should be interpretedas including the phrase “configured to.” Reciting a component that isconfigured to perform one or more tasks is expressly intended not toinvoke 35 U.S.C. § 112 paragraph (f), interpretation for that component

It will be apparent to those skilled in the art that variousmodifications and variations can be made to the present inventivetechnology without departing from the spirit and scope of thedisclosure. Since modifications, combinations, sub-combinations andvariations of the disclosed embodiments incorporating the spirit andsubstance of the inventive technology may occur to persons skilled inthe art, the inventive technology should be construed to includeeverything within the scope of the appended claims and theirequivalents.

Provided below are non-limiting examples illustrating certain aspects orfeatures of the present disclosure.

EXAMPLES Example 1: Prophetic Implantation Procedure

An example of an implant procedure that may be used to implant animplantable cranial medical device and associated devices is describedin this example. The implantable cranial medical device may be packagedwith a dual lumen brain catheter and accessories, such as screws, toolsfor use with the screws, an external catheter compression fitting, andthe like. Other generally available accessories to add in the navigationand implantation are specified here but not included in the Kit. Theimplantable cranial medical device may be compatible with and intendedto be used with the AxiEM™ electromagnetic technology forStealthStation® Navigation System (Medtronic Inc.) and theIntraventricular Disposable Introducer Set™ (B. Braun Aesculapdivision). The trajectory site of origin on the skull and lengthcatheter may be finalized during the surgical planning with thenavigation system.

The trajectory may be made with the aid of a 10 French IntraventricularDisposable Introducer (also known as Peel Away Sheath) which facilitatesthe process of aiming and introducing the AxiEM navigation stylet, and(secondly) the brain catheter, into the lateral ventricle. The depthscaling on the Disposable Introducer increases the security and controlwhile introducing the AxiEM stylet. The Sheath of the introducerprotects the cerebral tissue while inserting and withdrawing the AxiEMstylet during navigation. The round and blunt obturator tip on theDisposable Introducer ensures less traumatic insertion into the brain.The Disposable Introducer is also easy to peel with side handles oncethe catheter is in place.

After the trajectory is set with the Disposable introducer and AxiEMstylet, the Cranial Port, connected to the cranial catheter, may belowered into the inner lumen of the temporary sheath. The sheath maythen be removed. The upper flange portion of the implantable cranialmedical device may be fastened to the skull with cranial screws. Theexternal catheter may be connected to the port after it is tunneled froma separate infusion device, such as an implantable pump. A compressionfitting may be slid over the external catheter towards the implantablecranial medical device to securely retain the external catheter relativeto the implantable cranial medical device.

The following list provides some additional details:

-   1. Subjects will undergo a preoperative high-resolution MRI or CT    scan of the brain for surgical planning.-   2. Subject is positioned supine on the operating table and the head    is turned as needed for Stealth AxiEM utilization.-   3. Stealth AxiEM System is registered to the patient and multiple    head touch points are utilized as part of the setup and registration    of the stealth. Using the Stealth planning software, the location    for the tip of the brain catheter after placement is chosen to be 1    cm above and 1 cm proximal to the ipsilateral foramen of Monro. The    entry point is chosen to be Kochers Point via anatomic landmarks and    by referencing imaging. The resultant trajectory is then reviewed    and confirmed to avoid sulcal boundaries and cortical vessels and    planned to traverse a gyrus. Small modifications should be made to    the final entry point to facilitate this goal.-   4. A curvilinear incision is made over the entry point for the port    to be placed under the scalp allowing for room to tunnel from the    abdomen the proximal pump tubing using standard technique.-   5. A burr hole is placed over the identified entry point using a    standard 14 mm perforator and the dura is cauterized. If an    implantable infusion device and associated external catheter are    used, the manufacturer’s instructions for implanting the infusion    device and tunneling the external catheter should be followed.-   6. AxiEM Stylet (9733605 AxiEM™ Non-invasive shunt kit, Medtronic    Inc.) is placed in the obturator of a 10 French Intraventricular    Disposable Introducer Sheath (PaediScope™ PF010A, B. Braun) ------    Place Obturator/AxiEM within the sheath. A suture is placed around    the AxiEM to enable maximum penetration during advancement to target    but does not proceed beyond planned target location in the    ventricle. During placement of AxiEM in sheath in to target    location, endeavor to minimize CSF loss as possible.-   7. Confirm trajectory guidelines and target guidelines are met (see    above #4)-   8. The dura is opened in a cruciate fashion and leaflets are    cauterized. Pia arachnoid is cauterized and opened.-   9. Connect disposable tubing to external catheter connector on    implantable cranial medical device. Flush second fluid path of    implantable cranial medical device with 0.250 milliliters per second    slowly over 2 minutes. Remove disposable tubing and connect external    catheter to external catheter connector.-   10. The sheath and AxiEM stylet are advanced towards the target    using navigation trajectory and guidance views and the sheath and    Axiem left in place just at the target point.-   11. The two leafs of the sheath are peeled back and secured to the    drape and care is taken to avoid movement of the sheath or the AxiEM    tip within the brain.-   12. The connected implantable cranial medical device and dual lumen    brain catheter are prepped for insertion.-   13. At the same time, the AxiEM and obturator is removed, and the    sheath left in place just before the target point. The dual lumen    brain catheter is placed within the sheath to the depth of the    target location.-   14. The upper flange portion of the implantable cranial medical    device is held against the skull.-   15. Loss of CSF is estimated and recorded after CSF is gently    aspirated if needed as per the usual technique for sampling CSF from    a shunt or an ommaya port. Send specimen as needed for routine CSF    labs (anticipate > 2 milliliters of CSF total).-   16. The peel away sheath is removed while holding the cranial port    against bone.-   17. Install self-tapping cranial screws around the implantable    cranial medical device and burr hole to secure the implantable    cranial medical device to the skull.-   18. Confirm proper placement, that the tip of double lumen brain    catheter is in the ventricle, by one or both of CSF return and    imaging including CT scan, O-arm or contrast with fluoro.-   19. Verify integrity of ligatures at all junctions to prevent    obstruction of the external catheter lumen and tears or abrasions of    the tubing of external catheter.-   20. Suture skin.

Example 2: Prophetic Aspiration Procedure

An example of a procedure that may be used to aspirate CSF is providedin this example. The procedure includes:

-   1. After providing the purpose, risks and benefits, and steps of the    procedure obtain informed consent from the patient or appropriate    legal designee.-   2. Wash hands. Don sterile gloves.-   3. Scrub site with chlorhexadine or per site standard operating    procedure (SOP).-   4. Insert a 25-gauge butterfly needle directly into the port of the    implantable cranial medical device at a perpendicular angle to skin.    Angle needle at 30 --- 45 degrees from the skin and avoid being up    against the skin.-   5. Aspirate fluid into syringe slowly (not more than 1 ml per    minute).-   6. Limit the total volume aspirated at each tapping to no more than    7 ml. The initial puncture should not exceed 7 ml in volume and not    more than 7 ml/day.-   7. Send sample for culture, cell count, glucose, protein, and other    biomarkers as requested by physician.-   21. Remove needle and hold firm pressure for 2 minutes or until CSF    leakage from skin stops. Clean chlorhexadine from the skin after the    procedure.

Following the procedure, the subject should be assessed for possibleside-effects. For example, the subject should be observed for signs ofthe following complications: local skin breakdown; intravascular fluiddepletion; hypoproteinemia; hyponatremia, wound or device infections;and CSF leak from puncture site.

The following should be documented: pretreatment evaluation, informedconsent, timeout, procedure, including type and size of needle, patientresponse, characteristics of CSF, amount of CSF withdrawn, what testsordered on specimens, subject follow-up instructions includinganti-emetics if necessary, as well as any complications.

All abnormal or unexpected laboratory findings should be reviewed by aphysician.

Example 3: ICVRx Implantable Cranial Device from Cerebral Therapeutics,Inc

The implantable cranial medical devices described herein may be a partof an infusion system that enables intracerebroventricular (ICV)delivery of therapeutic agents, including investigational medicines,into the cerebrospinal fluid (CSF) for treatment of diseases of thecentral nervous system (CNS). The devices may also be used forwithdrawal of CSF for suitable purposes, such as biomarker, drug or drugmetabolite concentration, routine laboratory and safety analysis. Thecomplete infusion system in clinical use may include an implantable pumpand pump catheter, joined together with the implantable cranial medicaldevice and dual lumen cranial catheter.

One such implantable cranial implantable medical device and dual lumencatheter is the ICVRx Cranial Port and Dual Lumen Cranial Catheter fromCerebral Therapeutics, Inc. The ICVRx Cranial Port and Dual LumenCranial Catheter is currently under investigational use and includes amachined titanium access port and dual lumen intracranial catheter madefrom radiopaque tubing with a an embedded radiopaque (tantalum) tip. Thedual function of the ICVRx Cranial Port and Dual Lumen Cranial Cathetersupports continuous infusion of therapeutic agents into, and periodicaspiration of CSF out of, the lateral ventricle of the brain. AspiratedCSF may be used to monitor for early signs of infection (e.g.,meningitis), drug concentration, markers of disease progression, and thelike. The ICVRx Cranial Port and Dual Lumen Cranial Catheter is designedto have the advantages of both an Ommaya reservoir and a catheterfixation device for CNS infusion in a single small, low profile implantthat can be placed efficiently and accurately by a neurosurgical team.The cranial dual lumen catheter has radiopaque characteristics to aid inlocalization by imaging after surgical placement.

The design and construction of the ICVRx Cranial Port and Dual LumenCranial Catheter is intended to improve on existing methods and devicesincluding Ommaya and Rickham reservoirs. The ICVRx Cranial Port and DualLumen Cranial Catheter is designed to withstand long term implantationand use. As such, it should be compatible with safety and regulatoryrequirements for long term implant including biocompatibility,functional testing, periodic CSF sampling and robust against activepatient use.

Design and construction of the ICVRx device has a focus on separatinginfusion of therapeutic agent from aspiration of CSF. FIG. 23 showsseparated lumens within the catheter for infusing (purple) andaspiration (green). Separation of the infusion and sampling lumensensures no, or very little, mixing occurs and that the sample CSFrepresents the proportions of drug distribution actually seen in theventricle. The ICRVx Cranial Port and Dual Lumen Cranial Catheter ismade from material suitable for long term implantation such as titaniumand silicone (septum), as well as a polycarbonate polyurethane for thecatheter.

Non-clinical bench testing for the catheter demonstrates its ability forlong term use. Testing for flow path construction includedpreconditioning with over 1000 cycles of catheter attachment fatiguefollowed by high pressure burst testing with requirements greater than80 psi for burst. In addition, after conditioning, all catheterattachment exceeded 5N detachment requirements.

For sampling the cerebrospinal fluid through the catheter, the port isbuilt with a robust silicone reservoir. This reservoir was tested for500 punctures with a non-coring sampling needle and still maintained aleak-free seal demonstrated by pressure testing to 80 psi aftercompletion of punctures. This allows frequent CSF sampling whilemaintaining reservoir integrity and potentially reducing the infectionrisk.

Attachment of the ICVRx port to the skull is performed using cranialbone screws comment to orthopedic skull plating. These screws weretested to demonstrate equivalent or better performance including boneretention, torque to shear and tensile strength.

Initial implants have been performed as part of Phase 2B study. FIG. 24is capture as part of that study and demonstrates the radiopacity of thedevice under x-ray imaging. Note the port at the skull as well as thecatheter path into the ventricle.

Cerebral Therapeutics’ proprietary ICVRx Cranial Port and Dual LumenCranial Catheter is currently in use in clinical study for infusion ofsodium valproate in cerebral ventricles for treatment of refractoryepilepsy. The device is designed and tested to support chronic implantand long-term use for infusing therapeutics directly into the ventricle.

What is claimed is:
 1. A method comprising: delivering a therapeuticfluid to a brain of a patient via a catheter, wherein the therapeuticfluid comprises valproic acid or a pharmaceutically acceptable saltthereof, and wherein the catheter comprises one or more therapeuticfluid contact regions, the one or more fluid contact regions comprisinga polyurethane polymer, polyolefin, polyethylene, fluorinated polymer,or combinations thereof.
 2. The method of claim 1, wherein the cathetercomprises a polyurethane polymer.
 3. The method of claim 2, wherein thepolyurethane polymer comprises a hard segment and a soft segment,wherein the hard segment comprises a polymeric isocyanate and the softsegment comprises a polymeric polyol.
 4. The method of claim 3, whereinthe polymeric isocyanate comprises an aromatic isocyanate, an aliphaticisocyanate, or both.
 5. The method of claim 4, wherein the polymericpolyol comprises a polyether, polyester, or both.
 6. The method of claim3, wherein the polymeric polyol comprises a polyether, polyester, orboth.
 7. The method of claim 2, wherein the polyurethane polymercomprises an aromatic isocyanate, an aliphatic isocyanate, or both. 8.The method of claim 2, wherein the polyurethane polymer comprisespolyether, polycarbonate, or both.
 9. The method of claim 2, wherein thepolyurethane polymer comprises polycarbonate.
 10. The method of claim 2,wherein the polyurethane polymer has a Shore A hardness in a range from70A to 110A.
 11. The method of claim 2, wherein the polyurethane polymerhas a Shore D hardness in a range from 30D to 70D.
 12. The method ofclaim 1, wherein the catheter comprises a polyurethane hard segment anda polycarbonate soft segment.
 13. The method of claim 1, wherein thecatheter comprises a fluorinated polymer.
 14. The method of claim 13,wherein the fluorinated polymer is a homopolymer of polyvinylidenedifluoride (PVDF), a copolymer of PVDF, a copolymer oftetrafluoroethylene and hexafluoropropylene, orpolychlorotrifluoroethylene.
 15. The method of claim 1, wherein theconcentration of the valproic acid or the pharmaceutically acceptablesalt thereof in the therapeutic fluid is 10 mg/ml to 500 mg/ml or 50mg/ml to 450 mg/ml.
 16. The method of claim 1, wherein the patient hasepilepsy.